Dr. Michael Fowler is a Professor of Cardiovascular Medicine at Stanford Hospital & Clinics.

Dr. Fowler attended the Charing Cross Hospital Medical School, London, England. He has been elected to be a fellow in the Royal College of Physicians. He came to Stanford University on a British Heart Foundation, American Heart Association reciprocal fellowship award.

Dr. Fowler was appointed to the faculty in 1982. He is the Medical Director of the Heart Failure Program at Stanford University School of Medicine and Medical Director of the Stanford Cardiomyopathy Center.

Dr. Fowler has specialized in the treatment and research related to heart failure for over 30 years. He played an important role in the development of beta blocking drugs to treat heart failure and has also participated in most and the major studies that have led to our current comprehensive treatment for heart failure with drugs and devices. He is an expert in evaluating patients who may benefit from cardiac transplantation or mechanical support therapy.

Clinical Focus

  • Cardiology (Heart)
  • Heart and Lung Transplantation
  • Heart Failure
  • Cardiomyopathy
  • Cardiovascular Disease

Academic Appointments

Administrative Appointments

  • Clinical Asst. Prof. of Medicine, Stanford University Medical Center (1984 - 1986)
  • Co-Director, Cardiac Advanced Therapies Clinic, Stanford University Medical Center (1984 - 1991)
  • Co-Director, Coronary Care Unit, Stanford University Medical Center (1986 - 1991)
  • Assistant Professor of Medicine, CardiovascularMedicine, Stanford University Medical Center (1986 - 1993)
  • Co-Director, Heart Failure Clinic, Stanford University Medical Center (1991 - 2001)
  • Assoc. Prof. of Medicine, CardiovascularMedicine, Stanford University Medical Center (1993 - 1999)
  • Professor of Medicine, CardiovascularMedicine, Stanford University Medical Center (1999 - Present)
  • Director, Heart Failure Program, Stanford University Medical Center (2001 - Present)
  • Medical Director, CardiomyopathyCenter, Stanford University Medical Center (2001 - Present)

Professional Education

  • Fellowship:Stanford University School of Medicine Registrar (1984) CA
  • Residency:Brighton and Sussex Medical School (1979) England
  • Residency:Kent and Canterbury Hospital (1977) England
  • Internship:New Charing Hosp - London (1976)
  • Medical Education:Charing Cross Hospital Medical School (1975) UK

Research & Scholarship

Current Research and Scholarly Interests

Adrenergic nervous system; beta-adrenergic function in, heart failure; drugs in heart failure.

Clinical Trials

  • Study of the Effect of Sitagliptin on Glucose (Sugar) Metabolism in Patients With Heart Failure Not Recruiting

    This study will investigate the effects of sitagliptin, a medicine commonly used to treat type 2 diabetes, on the utilization of glucose by the heart in patients with heart failure which is not due to heart attacks. We hope to determine whether improving the heart's ability to use glucose in the blood may help improve the function of the heart as well. If so, this may suggest that even people who do not have frank diabetes but who do have heart failure may benefit from using this medication. This study will also investigate the effect of sitagliptin on the body's use of sugar, and of the effect of sitagliptin on blood flow to the heart.

    Stanford is currently not accepting patients for this trial. For more information, please contact Ronald Witteles, MD, 650-498-4343.

    View full details


2018-19 Courses


All Publications

  • Dipeptidyl Peptidase 4 Inhibition Increases Myocardial Glucose Uptake in Nonischemic Cardiomyopathy JOURNAL OF CARDIAC FAILURE Witteles, R. M., Keu, K. V., Quon, A., Tavana, H., Fowler, M. B. 2012; 18 (10): 804-809


    Glucose and fatty acids comprise the primary substrates for myocardial energy metabolism. The normal myocardium switches toward glucose metabolism in the setting of stress; the inability to affect such a switch is a fundamental mechanism behind "diabetic" or "insulin-resistant" cardiomyopathy. The purpose of this mechanistic study was to evaluate the effects of treatment with the dipeptidyl peptidase (DPP) 4 inhibitor sitagliptin on myocardial glucose uptake in patients with nonischemic cardiomyopathy.Twelve nondiabetic subjects with nonischemic cardiomyopathy underwent metabolic testing and assessment of myocardial glucose uptake by (18)F-fluorodeoxyglucose positron-emission tomographic/computerized tomographic imaging at baseline and after 4 weeks of sitagliptin therapy. Sitagliptin therapy resulted in a significant increase in myocardial glucose uptake (19% increase; P = .04). Although most patients had at least a slight increase in glucose uptake, there was an overall bimodal response, with 6 patients ("responders") demonstrating large increases (>20%) in glucose uptake and 6 patients ("nonresponders") demonstrating <5% increases or slight decreases. Triglyceride-high-density lipoprotein ratios significantly dropped in the 6 responders compared with the 6 nonresponders (P < .02).Therapy with the DPP-4 inhibitor sitagliptin results in increased myocardial glucose uptake in nondiabetic patients with nonischemic cardiomyopathy.

    View details for DOI 10.1016/j.cardfail.2012.07.009

    View details for PubMedID 23040117

  • Chemotherapy-Associated Cardiotoxicity: How Often Does it Really Occur and How Can it Be Prevented? HEART FAILURE CLINICS Witteles, R. M., Fowler, M. B., Telli, M. L. 2011; 7 (3): 333-?


    Cardiotoxicity remains the limiting factor for many forms of cancer therapy and is the focus of growing research and clinical emphasis. This article outlines the current clinical evidence for left ventricular dysfunction and heart failure for the two most important classes of cardiotoxic chemotherapeutic agents, examines the potential pitfalls that have led to underestimated rates of left ventricular dysfunction from these agents, and reviews strategies for screening for and providing prophylaxis against chemotherapy-associated left ventricular dysfunction.

    View details for DOI 10.1016/j.hfc.2011.03.005

    View details for PubMedID 21749885

  • GENETIC DETERMINANTS OF DRAMATIC IMPROVEMENT IN LEFT VENTRICULAR FUNCTION IN PATIENTS WITH HEART FAILURE 60th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC) / I2 Summit / ACCF/Herman K. Gold Young Investigator's Award in Molecular and Cellular Cardiology Perez, M. V., Pavlovic, A., Wheeler, M. T., Dewey, F. E., Bernstein, D., Fowler, M. B., Robbins, R. C., Quertermous, T., Chan, K., Absher, D., Ho, M., Cretti, E., Southwick, A., Rosenthal, D., Myers, R. M., Heidenreich, P., Garrett, L., Sedehi, D., Kao, D., Salisbury, H., Ashley, E. A. ELSEVIER SCIENCE INC. 2011: E2041–E2041
  • Measurement Precision in the Optimization of Cardiac Resynchronization Therapy CIRCULATION-HEART FAILURE Turcott, R. G., Witteles, R. M., Wang, P. J., Vagelos, R. H., Fowler, M. B., Ashley, E. A. 2010; 3 (3): 395-404


    Cardiac resynchronization therapy improves morbidity and mortality in appropriately selected patients. Whether atrioventricular (AV) and interventricular (VV) pacing interval optimization confers further clinical improvement remains unclear. A variety of techniques are used to estimate optimum AV/VV intervals; however, the precision of their estimates and the ramifications of an imprecise estimate have not been characterized previously.An objective methodology for quantifying the precision of estimated optimum AV/VV intervals was developed, allowing physiologic effects to be distinguished from measurement variability. Optimization using multiple conventional techniques was conducted in individual sessions with 20 patients. Measures of stroke volume and dyssynchrony were obtained using impedance cardiography and echocardiographic methods, specifically, aortic velocity-time integral, mitral velocity-time integral, A-wave truncation, and septal-posterior wall motion delay. Echocardiographic methods yielded statistically insignificant data in the majority of patients (62%-82%). In contrast, impedance cardiography yielded statistically significant results in 84% and 75% of patients for AV and VV interval optimization, respectively. Individual cases demonstrated that accepting a plausible but statistically insignificant estimated optimum AV or VV interval can result in worse cardiac function than default values.Consideration of statistical significance is critical for validating clinical optimization data in individual patients and for comparing competing optimization techniques. Accepting an estimated optimum without knowledge of its precision can result in worse cardiac function than default settings and a misinterpretation of observed changes over time. In this study, only impedance cardiography yielded statistically significant AV and VV interval optimization data in the majority of patients.

    View details for DOI 10.1161/CIRCHEARTFAILURE.109.900076

    View details for PubMedID 20176716

  • Rosiglitazone Increases Myocardial Glucose Metabolism in Insulin-Resistant Cardiomyopathy JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Kao, D. P., Witteles, R. M., Quon, A., Wu, J. C., Gambhir, S. S., Fowler, M. B. 2010; 55 (9): 926-927

    View details for DOI 10.1016/j.jacc.2009.08.085

    View details for Web of Science ID 000274865100015

    View details for PubMedID 20185047

  • Dyssynchrony Assessment with Tissue Doppler Imaging and Regional Volumetric Analysis by 3D Echocardiography Do Not Predict Long-Term Response to Cardiac Resynchronization Therapy. Cardiology research and practice Kuppahally, S. S., Fowler, M. B., Vagelos, R., Wang, P., Al-Ahmad, A., Hsia, H., Liang, D. 2010; 2011: 568918-?


    Background. Currently there are no reliable predictors of response to cardiac resynchronization therapy (CRT) before implantation. We compared pre-CRT left ventricular (LV) dyssynchrony by tissue Doppler imaging (TDI) and regional volumetric analysis by 3-dimensional transthoracic echocardiography (3DTTE) in predicting response to CRT. Methods. Thirty-eight patients (79% nonischemic cardiomyopathy) with symptomatic heart failure who underwent CRT were enrolled. Clinical and echocardiographic responses were defined as improvement in one NYHA class and reduction in LV end-systolic volume by ≥15% respectively. Functional status was assessed by Minnesota Living with Heart Failure questionnaire and 6-minute walk distance. Results. In 33 patients, after CRT for 7.86 ± 2.27 months, there were 24 (73%) clinical and 19 (58%) echocardiographic responders. Functional parameters, LV dimensions, volumes and synchrony by TDI and 3DTTE improved significantly in responders. There was no difference in the number of responders and nonresponders when cut-off values for dyssynchrony by different measurements validated in other trials were applied. Area under receiver-operating-characteristic curve ranged from 0.4 to 0.6. Conclusion. CRT improves clinical and echocardiographic parameters in patients with systolic heart failure. The dyssynchrony measurements by TDI and 3DTTE are not comparable and are unable to predict response to CRT.

    View details for DOI 10.4061/2011/568918

    View details for PubMedID 21234100

    View details for PubMedCentralID PMC3014673

  • Worsening of Left Ventricular End-Systolic Volume and Mitral Regurgitation without Increase in Left Ventricular Dyssynchrony on Acute Interruption of Cardiac Resynchronization Therapy ECHOCARDIOGRAPHY-A JOURNAL OF CARDIOVASCULAR ULTRASOUND AND ALLIED TECHNIQUES Kuppahally, S. S., Fowler, M. B., Vagelos, R., Wang, P., Al-Ahmad, A., Paloma, A., Liang, D. 2009; 26 (7): 759-765


    Responders to cardiac resynchronization therapy (CRT) have greater left ventricular (LV) dyssynchrony than nonresponders prior to CRT.We conducted this study to see whether the long term responders have more worsening of LV dyssynchrony and LV function on acute interruption of CRT.We identified 22 responders and 13 nonresponders who received CRT as per standard criteria for 23.73 +/- 7.9 months (median 24.5 months). We assessed the acute change in LV function, mitral regurgitation (MR) and compared LV dyssynchrony in CRT on and off modes.On turning off CRT, there was no significant worsening of LV dyssynchrony in both responders and nonresponders. The dyssynchrony measurements by SPWMD, TDI and 3D echocardiography did not correlate significantly. LVESV increased (p = 0.02) and MR (p = 0.01) worsened in CRT-off mode in responders only without significant change in LVEF or LV dimensions. Discussion andIn long-term responders to CRT, there is alteration in the function of remodeled LV with acute interruption of CRT, without significant worsening of LV dyssynchrony. The role of different echocardiographic parameters in the assessment of LV dyssynchrony remains controversial. Even after long-term CRT reversely remodels the LV, the therapy needs to be continued uninterrupted for sustained benefits.

    View details for DOI 10.1111/j.1540-8175.2008.00887.x

    View details for Web of Science ID 000268457100002

    View details for PubMedID 19558521

  • Hypertension, heart failure, and beta-adrenergic blocking drugs JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Fowler, M. B. 2008; 52 (13): 1073-1075

    View details for DOI 10.1016/j.jacc.2008.06.032

    View details for Web of Science ID 000259290700006

    View details for PubMedID 18848140

  • Evaluation of Polymorphisms in Candidate Genes in the Dramatic Response to Pharmacologic Therapy of Heart Failure Basic Cardiovascular Sciences Conference Wheeler, M. T., Pavlovic, A., Dewey, F., Perez, M., Absher, D., Ho, M. Y., Cretti, E., Southwick, A., Rosenthal, D. N., Bernstein, D., Myers, R. M., Heidenreich, P. A., Fowler, M. B., Robbins, R. C., Ashley, E. A. LIPPINCOTT WILLIAMS & WILKINS. 2008: E64–E65
  • Insulin-resistant cardiomyopathy JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Witteles, R. M., Fowler, M. B. 2008; 51 (2): 93-102


    Increasing evidence points to insulin resistance as a primary etiologic factor in the development of nonischemic heart failure (HF). The myocardium normally responds to injury by altering substrate metabolism to increase energy efficiency. Insulin resistance prevents this adaptive response and can lead to further injury by contributing to lipotoxicity, sympathetic up-regulation, inflammation, oxidative stress, and fibrosis. Animal models have repeatedly demonstrated the existence of an insulin-resistant cardiomyopathy, one that is characterized by inefficient energy metabolism and is reversible by improving energy use. Clinical studies in humans strongly support the link between insulin resistance and nonischemic HF. Insulin resistance is highly prevalent in the nonischemic HF population, predates the development of HF, independently defines a worse prognosis, and predicts response to antiadrenergic therapy. Potential options for treatment include metabolic-modulating agents and antidiabetic drugs. This article reviews the basic science evidence, animal experiments, and human clinical data supporting the existence of an "insulin-resistant cardiomyopathy" and proposes specific potential therapeutic approaches.

    View details for DOI 10.1016/j.jacc.2007.10.021

    View details for PubMedID 18191731

  • Impact of nesiritide on renal function in patients with acute decompensated failure an pre-existing renal dysfunction - A randomized, double-blind, placebo-controlled clinical trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Witteles, R. M., Kao, D., Christopherson, D., Matsuda, K., Vagelos, R. H., Schreiber, D., Fowler, M. B. 2007; 50 (19): 1835-1840


    Our purpose was to evaluate the impact of nesiritide on renal function in patients with acute decompensated heart failure and baseline renal dysfunction.Although nesiritide is approved for the treatment of acute decompensated heart failure, retrospective analyses have raised concerns that it may cause worsened renal function. To date, no randomized clinical trials have prospectively evaluated this issue.Consecutive patients with acute decompensated heart failure and baseline renal dysfunction were enrolled in this randomized, double-blind, placebo-controlled clinical trial. Subjects were randomized to receive nesiritide (0.01 microg/kg/min with or without a 2-microg/kg bolus) or placebo (5% dextrose in water) for 48 h in addition to their usual care. Predefined primary end points of the trial were a rise in serum creatinine by > or =20% and change in serum creatinine.Seventy-five patients were enrolled (39 nesiritide, 36 placebo). The groups had similar baseline age (74.9 vs. 75.5 years, respectively), blood pressure (123/64 vs. 125/64 mm Hg) and serum creatinine (1.82 vs. 1.86 mg/dl). There were no significant differences in the incidence of a 20% creatinine rise (23% vs. 25%) or in the change in serum creatinine (-0.05 vs. +0.05 mg/dl). There were no significant differences in the secondary end points of change in weight (-2.19 vs. -1.58 kg), intravenous furosemide (125 vs. 107 mg), discontinuation of the infusion due to hypotension (13% vs. 6%), or 30-day death/hospital readmission (33% vs. 25%).In this randomized, double-blind, placebo-controlled clinical trial, nesiritide had no impact on renal function in patients with acute decompensated heart failure. (BNP-CARDS trial;; NCT00186329).

    View details for DOI 10.1016/j.jacc.2007.03.071

    View details for PubMedID 17980248

  • Outcome in cardiac recipients of donor hearts with increased left ventricular wall thickness AMERICAN JOURNAL OF TRANSPLANTATION Kuppahally, S. S., Valantine, H. A., Weisshaar, D., Parekh, H., Hung, Y. Y., Haddad, F., Fowler, M., Vagelos, R., Perlroth, M. G., Robbins, R. C., Hunt, S. A. 2007; 7 (10): 2388-2395


    The ongoing shortage of donors for cardiac transplantation has led to a trend toward acceptance of donor hearts with some structural abnormalities including left ventricular hypertrophy. To evaluate the outcome in recipients of donor hearts with increased left ventricular wall thickness (LVWT), we retrospectively analyzed data for 157 cardiac donors and respective recipients from January 2001 to December 2004. There were 47 recipients of donor heart with increased LVWT >or=1.2 cm, which constituted the study group and 110 recipients of a donor heart with normal LVWT < 1.2 cm that formed the control group. At 3 +/- 1.5 years, recipient survival was lower (50% vs. 82%, p = 0.0053) and incidence of allograft vasculopathy was higher (50% vs. 22%, p = 0.05) in recipients of donor heart with LVWT > 1.4 cm as compared to LVWT 1.4 cm (p = 0.003), recipient preoperative ventricular assist device (VAD) support (p = 0.04) and bypass time > 150 min (p = 0.05) were predictors of reduced survival. Our results suggest careful consideration of donor hearts with echocardiographic evidence of increased LVWT in the absence of hypovolemia, because they may be associated with poorer outcomes; such hearts should potentially be reserved only for the most desperately ill recipients.

    View details for DOI 10.1111/j.1600-6143.2007.01930.x

    View details for Web of Science ID 000249167000022

    View details for PubMedID 17845572

  • beta-blocker dosing in community-based treatment of heart failure AMERICAN HEART JOURNAL Fowler, M. B., Lottes, S. R., Nelson, J. J., Lukas, M. A., Gilbert, E. M., Greenberg, B., Massie, B. M., Abraham, W. T., Franciosa, J. A. 2007; 153 (6): 1029-1036


    Community patients with heart failure (HF) are older, less often treated by HF specialists, and have more comorbidity than those in randomized clinical trials. These differences might affect beta-blocker prescribing in HF.To explore patterns of beta-blocker prescribing for HF in the community and their association with outcomes, we determined carvedilol doses at end titration in 4113 patients from a community-based beta-blocker HF registry according to physician and patient characteristics, HF severity, and rates of hospitalization and death.Female sex, age > or = 65 years, and left ventricular ejection fraction > or = 35% were associated with lower beta-blocker doses. Average daily dose of beta-blocker was lower with worse baseline New York Heart Association class. More patients of cardiologists achieved carvedilol doses > or = 25 mg twice daily, whereas in those of noncardiologists lower doses were more common. Relative risk of HF hospitalizations or all-cause death was significantly lower with higher doses of beta-blocker.Beta-blocker dosing in community HF appears lower than in randomized clinical trials, especially when prescribed by noncardiologists. At all doses, patients taking the beta-blocker carvedilol have a lower incidence of death and HF hospitalization than those discontinuing it, regardless of physician type in the community setting.

    View details for DOI 10.1016/j.ahj.200.03.010

    View details for Web of Science ID 000247540600020

    View details for PubMedID 17540206

  • Comparison of outcomes and usefulness of carvedilol across a spectrum of left ventricular ejection fractions in patients with heart failure in clinical practice AMERICAN JOURNAL OF CARDIOLOGY Massie, B. M., Nelson, J. J., Lukas, M. A., Greenberg, B., Fowler, M. B., Gilbert, E. M., Abraham, W. T., Lottes, S. R., Franciosa, J. A. 2007; 99 (9): 1263-1268


    Heart failure (HF) in the community differs meaningfully from that in clinical trials, particularly the higher prevalence of patients with preserved left ventricular (LV) ejection fraction (EF) typically excluded from clinical trials, thus limiting knowledge of their responsiveness to beta-blocker therapy. From a community-based registry of 4,280 patients with HF starting treatment with the beta blocker carvedilol, we compared characteristics, carvedilol titration, and outcomes of patients according to LVEF >40% or <40% (as in clinical trials) and across the spectrum of LVEF <21%, 21% to 30%, 31% to 40%, and >40%. Patients with preserved EF (LVEF >40%) were older and more often women and hypertensive. Lower LVEF was associated with worse functional class and more HF hospitalizations in the previous year. Carvedilol dose decreased with increasing LVEF. Hospitalization rates for HF related inversely to LVEF before starting carvedilol therapy and decreased from the previous year in all LVEF groups during follow-up. Although 1-year mortality rate decreased from 8% with LVEF < or =20% to 6% with LVEF >40%, adjusted hazard ratios were not significantly different across LVEF groups. Thus, characteristics of community patients with HF vary across the spectrum of LVEF. Patients with HF and preserved EF treated with carvedilol in the community improve symptomatically and experience fewer HF hospitalizations after initiating carvedilol. In conclusion, without a control group, the effect of carvedilol on outcomes is not conclusive and trials of carvedilol in patients with HF and preserved EF should be undertaken.

    View details for DOI 10.1016/j.amjcard.2006.12.056

    View details for Web of Science ID 000246168600019

    View details for PubMedID 17478155

  • Why do we need to prevent right ventricular pacing? Progress in cardiovascular nursing Tsiperfal, A., Scheibly, K., Fowler, M. B., Chao, C. 2007; 22 (2): 108-109

    View details for PubMedID 17541323

  • The effect of gender on mortality or appropriate shock in patients with nonischemic cardiomyopathy who have implantable cardioverter-defibrillators PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY Chen, H. A., Hsia, H. H., Vagelos, R., Fowler, M., Wang, P., Al-Ahmad, A. 2007; 30 (3): 390-394


    As heart disease is increasingly recognized in women and as important studies have elucidated the benefit of implantable cardioverter defibrillators (ICDs) in patients with nonischemic cardiomyopathy (NICM), little is known regarding the effect of gender difference on arrhythmic risk in this population. We sought to determine if there are gender differences in arrhythmic risk and potential defibrillator benefit in patients with NICM.The records of 767 consecutive patients who underwent ICD implant at the Stanford Medical Center from 1984 to 2002 were reviewed. Only patients with NICM were considered (n = 201, 26.2%). Of these, 140 patients had clinical follow-up information available. Baseline variables were examined, including age, baseline heart rate, ejection fraction, and medications. We evaluated the time to first shock as well as all-cause mortality in this patient population. Kaplan-Meier survival curves were plotted, a log-rank test was used to evaluate significance, and Cox-proportional hazards test was used for multivariate analysis.There were 88 (62.9%) men and 52 (37.1%) women. Between male and female patients, there were no significant differences in baseline mean age (54.8 +/- 1.9 years vs 53.1 +/- 2.3 years, respectively), ejection fraction (35.2 +/- 2.0% vs 33.3 +/- 2.3%, respectively), and mean left ventricular end-diastolic dimension (6.4 +/- 0.3 cm vs 5.9 +/- 0.2 cm, respectively). Mean follow-up time was 30.8 months. Thirty-two male patients (36.4 +/- 0.05%) received appropriate shocks compared with 20 female patients (38.5 +/- 0.07%). Mean time to the first appropriate shock was 11.9 +/- 3.9 months for male patients and 21.3 +/- 5.8 months for female patients (P = 0.2). Nineteen male patients (21.6 +/- 0.05%) died or received heart transplant during the follow-up period compared with 6 female patients (11.5 +/- 0.04%) (P = 0.11).Male and female patients with NICM who received ICDs had similar rate of appropriate shock and mortality. In this population gender does not appear to be an important risk factor for mortality or arrhythmic events.

    View details for Web of Science ID 000244886500013

    View details for PubMedID 17367359

  • Emerging therapies for the management of decompensated heart failure - From bench to bedside JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY DeGoma, E. M., Vagelos, R. H., Fowler, M. B., Ashley, E. A. 2006; 48 (12): 2397-2409


    While pharmaceutical innovation has been highly successful in reducing mortality in chronic heart failure, this has not been matched by similar success in decompensated heart failure syndromes. Despite outstanding issues over definitions and end points, we argue in this paper that an unprecedented wealth of pharmacologic innovation may soon transform the management of these challenging patients. Agents that target contractility, such as cardiac myosin activators and novel adenosine triphosphate-dependent transmembrane sodium-potassium pump inhibitors, provide inotropic support without arrhythmogenic increases in cytosolic calcium or side effects of more traditional agents. Adenosine receptor blockade may improve glomerular filtration and diuresis by exerting a direct beneficial effect on glomerular blood flow while vasopressin antagonists promote free water excretion without compromising renal function and may simultaneously inhibit myocardial remodeling. Urodilatin, the renally synthesized isoform of atrial natriuretic peptide, may improve pulmonary congestion via vasodilation and enhanced diuresis. Finally, metabolic modulators such as perhexiline may optimize myocardial energy utilization by shifting adenosine triphosphate production from free fatty acids to glucose, a unique and conceptually appealing approach to the management of heart failure. These advances allow optimism not only for the advancement of our understanding and management of decompensated heart failure syndromes but for the translational research effort in heart failure biology in general.

    View details for DOI 10.1016/j.jacc.2006.08.039

    View details for Web of Science ID 000242916100001

    View details for PubMedID 17174176

  • Predictors of clinical outcomes in patients given carvedilol for heart failure AMERICAN JOURNAL OF CARDIOLOGY Greenberg, B., Lottes, S. R., Nelson, J. J., Lukas, M. A., Fowler, M. B., Massie, B. M., Abraham, W. T., Gilbert, E. M., Franciosa, J. A. 2006; 98 (11): 1480-1484


    Risk factors for outcomes in heart failure (HF) were derived from populations in clinical trials, at hospital discharge, or in localized geographic or socioeconomic strata before the widespread use of beta blockers. This study observed 4,280 patients in a community-based HF registry for 1 year after completing carvedilol titration. Independent risk factors for death, hospitalization for HF, or hospitalization for cardiovascular reasons other than HF were first identified by age-, gender-, and race-adjusted analyses, then by multivariate analysis adjusted simultaneously for all factors. Over this period, 7% of patients died, 11% were hospitalized for HF, 12% were hospitalized for other cardiovascular reasons, and 27% had > or =1 of these events. The most significant outcome predictors were New York Heart Association class III or IV, history of hospitalization for HF or other cardiovascular reasons, and angina pectoris, all associated with increased odds of having an adverse outcome (all p < or =0.001). The left ventricular ejection fraction was not a significant outcome predictor by multivariate analysis. The odds ratio for an adverse outcome was significantly reduced for patients with hypertensive or idiopathic causes of HF and for those whose physicians had graduated from medical school > or =24 years earlier compared with <14 years earlier (all p <0.005). In conclusion, easily obtained historical information predicts clinical outcomes in patients with HF in the year after initiating carvedilol. In this unselected community population, these historical factors were better predictors of risk than the left ventricular ejection fraction.

    View details for DOI 10.1016/j.amjcard.2006.06.050

    View details for Web of Science ID 000242595300013

    View details for PubMedID 17126654

  • Left ventricular dyssynchrony does not deteriorate acutely on cessation of cardiac resynchronization therapy in long term responders 10th Annual Scientific Meeting of the Heart-Failure-Society-of-America Kuppahally, S., Fowler, M., Wang, P., Vagelos, R., Al-Ahmad, A., Paloma, A., Liang, D. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2006: S76–S76
  • The effect of carvedilol on mortality risk in heart failure patients with diabetes: results of a meta-analysis CURRENT MEDICAL RESEARCH AND OPINION Bell, D. S., Lukas, M. A., Holdbrook, F. K., Fowler, M. B. 2006; 22 (2): 287-296


    Although beta-blocker therapy has been shown to improve survival in patients with chronic heart failure, this class of drugs tends to be underutilized in diabetic patients due to concerns about adverse metabolic effects, especially on glycemic control. No randomized clinical trial has specifically evaluated the effect of beta-blocker therapy on mortality in diabetic patients with heart failure. Previous meta-analyses combining results of heart failure trials with pharmacologically diverse beta-blockers suggest that the survival benefit in diabetic patients may be diminished compared to benefits in non-diabetic patients. However, some trial results indicate that carvedilol, which blocks beta1-, beta2-, and alpha1-receptors and is a potent antioxidant, may produce at least comparable effects in both patient groups.To evaluate the effect of carvedilol in patients with heart failure and diabetes, specifically to determine if the survival benefit of carvedilol demonstrated in heart failure trials was as great in the subgroups of patients with diabetes.A meta-analysis was performed that included 5757 patients with heart failure, 25% of whom had diabetes, from seven large placebo-controlled randomized trials with carvedilol. All large (> 100 patients) placebo-controlled, randomized trials with carvedilol in heart failure were included. The endpoint of all-cause mortality was examined in the overall population, patients without diabetes, and patients with diabetes. The number of patients needed to treat (NNT) for 1 year to prevent one death associated with carvedilol use in diabetic versus non-diabetic patients was also calculated. The log-rank test and the Cox proportional hazards regression were used to compare the event time distributions of carvedilol versus placebo with respect to the outcome of mortality.Similar survival benefits were seen with carvedilol use in diabetic and non-diabetic patients (relative risk reductions of 28% [95% confidence interval (CI) 3-46%; p = 0.03] and 37% [95% CI 22-48%; p < 0.001], respectively). There were no significant differences between the relative mortality risk reductions or the NNT with carvedilol use in diabetic versus non-diabetic patients. The NNT for 1 year to prevent one death was 23 for all patients, as well as for non-diabetic patients, and 25 for the diabetic group.This meta-analysis provides evidence that the same survival benefit may occur with carvedilol in heart failure patients with and without diabetes. The low NNT in the severe heart failure trial, COPERNICUS, and the diabetic subgroup in this meta-analysis suggests that severe heart failure patients and heart failure patients with diabetes may particularly derive benefit from therapy with carvedilol.

    View details for DOI 10.1185/030079906X80459

    View details for Web of Science ID 000236302200006

    View details for PubMedID 16466600

  • Cardiomyopathy of insulin resistance. Heart failure clinics Witteles, R. M., Fowler, M. B. 2006; 2 (1): 13-23

    View details for PubMedID 17386873

  • Are beta-blockers needed in patients receiving spironolactone for severe chronic heart failure? An analysis of the COPERNICUS study AMERICAN HEART JOURNAL Krum, H., Mohacsi, P., Katus, H. A., Tendera, M., Rouleau, J. L., Fowler, M. B., Coats, A. J., Roecker, E. B., Packer, M. 2006; 151 (1): 55-61


    The beneficial effects of beta-blockers and aldosterone receptor antagonists are now well established in patients with severe systolic chronic heart failure (CHF). However, it is unclear whether beta-blockers are able to provide additional benefit in patients already receiving aldosterone antagonists. We therefore examined this question in the COPERNICUS study of 2289 patients with severe CHF receiving the beta1-beta2/alpha1 blocker carvedilol compared with placebo.Patients were divided post hoc into subgroups according to whether they were receiving spironolactone (n = 445) or not (n = 1844) at baseline. Consistency of the effect of carvedilol versus placebo was examined for these subgroups with respect to the predefined end points of all-cause mortality, death or CHF-related hospitalizations, death or cardiovascular hospitalizations, and death or all-cause hospitalizations.The beneficial effect of carvedilol was similar among patients who were or were not receiving spironolactone for each of the 4 efficacy measures. For all-cause mortality, the Cox model hazard ratio for carvedilol compared with placebo was 0.65 (95% CI 0.36-1.15) in patients receiving spironolactone and 0.65 (0.51-0.83) in patients not receiving spironolactone. Hazard ratios for death or all-cause hospitalization were 0.76 (0.55-1.05) versus 0.76 (0.66-0.88); for death or cardiovascular hospitalization, 0.61 (0.42-0.89) versus 0.75 (0.64-0.88); and for death or CHF hospitalization, 0.63 (0.43-0.94) versus 0.70 (0.59-0.84), in patients receiving and not receiving spironolactone, respectively. The safety and tolerability of treatment with carvedilol were also similar, regardless of background spironolactone.Carvedilol remained clinically efficacious in the COPERNICUS study of patients with severe CHF when added to background spironolactone in patients who were practically all receiving angiotensin-converting enzyme inhibitor (or angiotensin II antagonist) therapy. Therefore, the use of spironolactone in patients with severe CHF does not obviate the necessity of additional treatment that interferes with the adverse effects of sympathetic activation, specifically beta-blockade.

    View details for DOI 10.1016/j.ahj.2005.03.054

    View details for Web of Science ID 000234485100009

    View details for PubMedID 16368292

  • Impact of angiotenisin-converting enzyme gene polymorphism on neurohormonal responses to high- versus low-dose enalapril in advanced heart failure AMERICAN HEART JOURNAL Tang, W. H., Vagelos, R. H., Yee, Y. G., Fowler, M. B. 2004; 148 (5): 889-894


    The impact of angiotensin-converting enzyme (ACE) gene polymorphism on neurohormonal dose response to ACE inhibitor therapy is unclear.ACE Insertion (I) or Deletion (D) genotype was determined in 74 patients with chronic heart failure who were randomly assigned to receive either high-dose or low-dose enalapril over a period of 6 months. Monthly pre-enalapril and post-enalapril neurohormone levels (serum ACE activity (sACE), plasma angiotensin II (A-II), plasma renin activity (PRA), and serum aldosterone (ALDO) were compared between genotype subgroups and between patients who received high- or low-dose enalapril within each genotype subgroup.At baseline, predose/postdose sACE and postdose PRA were significantly higher in the DD genotype. At 6-month follow-up, postdose sACE was reduced in a dose-dependent fashion in all three genotypes (P < .05). However, predose and postdose ALDO and A-II levels did not differ between each genotype subgroup at baseline or by enalapril dose within each genotype subgroup. ALDO escape and A-II reactivation were not affected by ACE genotype or enalapril dosage.Predose sACE were consistently higher in the DD genotype when compared with ID or II subgroups. Despite a dose-dependent suppression of sACE, there were no observed statistically significant differences in ALDO and A-II suppression or escape with escalating doses of enalapril within each subgroup.

    View details for DOI 10.1016/j.ahj.2004.05.020

    View details for Web of Science ID 000225045100023

    View details for PubMedID 15523323

  • Care management for low-risk patients with heart failure - A randomized, controlled trial ANNALS OF INTERNAL MEDICINE DeBusk, R. F., Miller, N. H., Parker, K. M., Bandura, A., Kraemer, H. C., Cher, D. J., West, J. A., Fowler, M. B., Greenwald, G. 2004; 141 (8): 606-613


    Nurse care management programs for patients with chronic illness have been shown to be safe and effective.To determine whether a telephone-mediated nurse care management program for heart failure reduced the rate of rehospitalization for heart failure and for all causes over a 1-year period.Randomized, controlled trial of usual care with nurse management versus usual care alone in patients hospitalized for heart failure from May 1998 through October 2001.5 northern California hospitals in a large health maintenance organization.Of 2786 patients screened, 462 met clinical criteria for heart failure and were randomly assigned (228 to intervention and 234 to usual care).Nurse care management provided structured telephone surveillance and treatment for heart failure and coordination of patients' care with primary care physicians.Time to first rehospitalization for heart failure or for any cause and time to a combined end point of first rehospitalization, emergency department visit, or death.At 1 year, half of the patients had been rehospitalized at least once and 11% had died. Only one third of rehospitalizations were for heart failure. The rate of first rehospitalization for heart failure was similar in both groups (proportional hazard, 0.85 [95% CI, 0.46 to 1.57]). The rate of all-cause rehospitalization was similar (proportional hazard, 0.98 [CI, 0.76 to 1.27]).The findings of this study, conducted in a single health care system, may not be generalizable to other health care systems. The overall effect of the intervention was minor.Among patients with heart failure at low risk on the basis of sociodemographic and medical attributes, nurse care management did not statistically significantly reduce rehospitalizations for heart failure or for any cause. Such programs may be less effective for patients at low risk than those at high risk.

    View details for PubMedID 15492340

  • beta-Blocker therapy for heart failure outside the clinical trial setting: Findings of a community-based registry AMERICAN HEART JOURNAL Franciosa, J. A., Massie, B. M., Lukas, M. A., Nelson, J. J., Lottes, S., Abraham, W. T., Fowler, M., Gilbert, E. M., Greenberg, B. 2004; 148 (4): 718-726


    beta-Blockers reduce morbidity and mortality rates in heart failure (HF) clinical trials, but it is unknown whether these findings persist in the community setting.A registry was created to survey tolerability and outcomes during initiation and 1-year follow-up of beta-blocker treatment with carvedilol in patients with HF treated by cardiologists (CARD) and primary care physicians (PCP) in the community.A total 4280 patients were enrolled (3121 by 259 CARD, 1159 by 129 PCP). Patient age averaged 67 +/- 13 years; 35% were women and 12% were black. The left ventricular ejection fraction averaged 31 +/- 12; New York Heart Association class was II-III in 86% and IV in 3%. Patients of PCP had higher left ventricular ejection fraction, were older, and more frequently were female, black, diabetic, hypertensive, and in New York Heart Association class III/IV. Minimal difficulty titrating carvedilol was noted by >80% of CARD and PCP. Significantly more CARD-treated patients reached carvedilol doses of 25 mg twice daily (49% vs 27%). Kaplan-Meier all-cause mortality rate was 8.5% at 1 year and did not differ between CARD-treated and PCP-treated patients (8.2% vs 9.3%, P =.254). At least one HF hospitalization occurred in 11% of patients during follow-up, compared with 28% in the preceding year.Community-based physicians use carvedilol with success approaching that of clinical trials. Overall mortality rates and HF hospitalizations were in the same low range as in clinical trials. Thus, it appears that results of clinical trials with carvedilol for HF can be translated to the community setting.

    View details for DOI 10.1016/j.ahj.2004.04.006

    View details for Web of Science ID 000224650900027

    View details for PubMedID 15459606

  • Insulin resistance in idiopathic dilated cardiomyopathy - A possible etiologic link JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Witteles, R. M., Tang, W. H., Jamali, A. H., Chu, J. W., Reaven, G. M., Fowler, M. B. 2004; 44 (1): 78-81


    This study was designed to quantify the prevalence of abnormal glucose tolerance and insulin resistance in patients with idiopathic dilated cardiomyopathy (IDCM).Insulin resistance is an independent risk factor for mortality in patients with heart failure (HF) and is a known risk factor for ischemic cardiomyopathy. Though potential physiologic links between insulin resistance and HF have been hypothesized, the relationship between insulin resistance and IDCM remains unclear.A total of 230 consecutive patients from a university HF clinic were screened for IDCM, the absence of diabetes mellitus, and the lack of significant co-morbid conditions. Oral glucose tolerance tests were performed in the 43 patients with IDCM who met these criteria, and their plasma glucose and insulin responses were compared with those of 40 healthy volunteers, matched for age, gender, and body mass index.Plasma glucose responses were higher during the oral glucose tolerance tests in patients with IDCM (p < 0.01), associated with significantly higher plasma insulin concentrations following the oral glucose challenge (p < 0.01). In addition, abnormalities of glucose tolerance were significantly (p < 0.05) more common in patients with IDCM (49% vs. 23%).Insulin resistance and abnormal glucose tolerance are more prevalent in patients with IDCM and represent potentially reversible metabolic derangements in these individuals.

    View details for DOI 10.1016/j.jacc.2004.03.037

    View details for PubMedID 15234411

  • Carvedilol prospective randomized cumulative survival (COPERNICUS) trial: Carvedilol in severe heart failure AMERICAN JOURNAL OF CARDIOLOGY Fowler, M. B. 2004; 93 (9A): 35B-39B


    The impact of carvedilol on the survival of patients with severe heart failure was examined in the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial. The trial recruited 2,289 patients with symptoms at rest or on minimal exertion despite therapy with angiotensin-converting enzyme inhibitors and a left ventricular ejection fraction of < or = 0.25. After an average follow-up period of 10.4 months, mortality was reduced by 34% in the carvedilol group. Carvedilol also reduced the number of days spent in the hospital for any cause by 27% and the number of days spent in the hospital for heart failure by 40%. Patients in the carvedilol group felt better and were less likely to have a serious adverse event. The benefits of carvedilol appeared early and were detected during the up-titration period.

    View details for DOI 10.1016/j.amjcard.2004.01.004

    View details for Web of Science ID 000221695900008

    View details for PubMedID 15144935

  • Influence of pretreatment systolic blood pressure on the effect of carvedilol in patients with severe chronic heart failure - The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Rouleau, J. L., Roecker, E. B., Tendera, M., Mohacsi, P., Krum, H., Katus, H. A., Fowler, M. B., COATS, A. J., Castaigne, A., Scherhag, A., Holcslaw, T. L., Packer, M. 2004; 43 (8): 1423-1429


    We sought to evaluate the influence of pretreatment systolic blood pressure (SBP) on the efficacy and safety of carvedilol in patients with chronic heart failure (CHF).Although beta-blockers reduce the risk of death in CHF, there is little reported experience with these drugs in patients with a low pretreatment SBP, who may respond poorly to beta-blockade.We studied 2,289 patients with severe CHF who participated in the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial.Compared with placebo, carvedilol improved the clinical status and reduced the risk of death and the combined risk of death or hospitalization for any reason, for a cardiovascular reason, or for worsening heart failure (p < 0.001 for all). The relative magnitude of these benefits did not vary as a function of the pretreatment SBP (all interaction: p > 0.10). However, because patients with the lowest SBP were at highest risk of an event, they experienced the greatest absolute benefit from treatment with carvedilol. The lower the pretreatment SBP, the more likely that patients would report an adverse event, be intolerant of high doses of the study drug, or require permanent withdrawal of treatment (p < 0.001 for all). However, these risks were primarily related to the severity of the underlying illness and not to treatment with carvedilol.The current study provides little support for concerns about using beta-blockers (particularly those with vasodilatory actions) in patients with severe CHF who have a low SBP. Pretreatment blood pressure can identify patients who have the greatest need for risk reduction with carvedilol.

    View details for DOI 10.1016/j.jacc.2003.11.037

    View details for Web of Science ID 000220881000016

    View details for PubMedID 15093878

  • How does myocardial inducible nitric oxide synthase gene expression relate to heart failure severity and to subsequent left ventricular reverse remodeling in patients with chronic heart failure? 53rd Annual Scientific Session of the American-College-of-Cardiology Tang, W. H., LOPEZ, F., Yee, Y. G., Mullin, A., Zhang, Y., Fowler, M. B. ELSEVIER SCIENCE INC. 2004: 155A–155A
  • Influence of carvedilol therapy on myocardial expression of inducible nitric oxide synthase (NOS2) and the contractile response to beta-adrenergic inotropic stimulation in patients with dilated cardiomyopathy 76th Annual Scientific Session of the American-Heart-Association Tang, W. H., LOPEZ, F., Lo, S. T., Yee, Y. G., Mullin, A., Zhang, Y., Fowler, M. B. LIPPINCOTT WILLIAMS & WILKINS. 2003: 412–12
  • Novel role for the potent endogenous inotrope apelin in human cardiac dysfunction CIRCULATION Chen, M. M., Ashley, E. A., Deng, D. X., Tsalenko, A., Deng, A., Tabibiazar, R., Ben-Dor, A., Fenster, B., Yang, E., King, J. Y., Fowler, M., Robbins, R., Johnson, F. L., Bruhn, L., McDonagh, T., Dargie, H., Yakhini, Z., Tsao, P. S., Quertermous, T. 2003; 108 (12): 1432-1439


    Apelin is among the most potent stimulators of cardiac contractility known. However, no physiological or pathological role for apelin-angiotensin receptor-like 1 (APJ) signaling has ever been described.We performed transcriptional profiling using a spotted cDNA microarray with 12 814 unique clones on paired samples of left ventricle obtained before and after placement of a left ventricular assist device in 11 patients. The significance analysis of microarrays and a novel rank consistency score designed to exploit the paired structure of the data confirmed that natriuretic peptides were among the most significantly downregulated genes after offloading. The most significantly upregulated gene was the G-protein-coupled receptor APJ, the specific receptor for apelin. We demonstrate here using immunoassay and immunohistochemical techniques that apelin is localized primarily in the endothelium of the coronary arteries and is found at a higher concentration in cardiac tissue after mechanical offloading. These findings imply an important paracrine signaling pathway in the heart. We additionally extend the clinical significance of this work by reporting for the first time circulating human apelin levels and demonstrating increases in the plasma level of apelin in patients with left ventricular dysfunction.The apelin-APJ signaling pathway emerges as an important novel mediator of cardiovascular control.

    View details for DOI 10.1161/01.CIR.0000091235.94914.75

    View details for PubMedID 12963638

  • Reduced myocardial brain natriuretic peptide expression and collagen deposition following ventricular assist device support for heart failure 52nd Annual Scientific Session of the American-College-of-Cardiology Fenster, B. E., Fowler, M. B., Yee, Y. G., Connolly, A., Tsao, P. S. ELSEVIER SCIENCE INC. 2003: 165A–165A
  • Physical activity patterns and exercise performance in cardiac transplant recipients. Journal of cardiopulmonary rehabilitation Myers, J., Gullestad, L., Bellin, D., Ross, H., Vagelos, R., Fowler, M. 2003; 23 (2): 100-106


    Cardiac transplantation (CTX) improves exercise tolerance, but CTX recipients still achieve only 50% to 70% of normal values for exercise capacity. Among the factors suggested to explain the reduced exercise tolerance in CTX recipients is deconditioning. Little is known about the relation between physical activity patterns and exercise test responses in CTX patients.Forty-seven CTX patients (mean age 47 +/- 12 years; mean 4.8 +/- 3.0 years after CTX) underwent maximal exercise testing and assessment of current and past physical activity patterns using a questionnaire. Energy expenditure from recreational and occupational activities over the last year and for adulthood were expressed in kcal/week and correlated with peak oxygen consumption (VO(2)), VO(2) at the ventilatory threshold, and the percentage of age-predicted peak VO(2) achieved.The patients reported expending a mean of approximately 1100 kcal/week in recreational activity, suggesting a moderate level of physical activity is maintained after CTX. The mean peak VO(2) achieved for the group was 17.2 +/- 5.2 mL/kg/min, corresponding to 59% +/- 14% of age-predicted exercise capacity. Significant but modest associations were observed between recreational energy expenditure during the last year and percentage of age-predicted peak VO(2) achieved (r = 0.34, P <.01), and VO(2) at the ventilatory threshold (r = 0.45, P <.01). Energy expenditure from blocks walked and stairs climbed per week was modestly associated with peak VO(2) (r = 0.36, P <.05), percentage of predicted peak VO(2) achieved (r = 0.39, P <.01), and VO(2) at the ventilatory threshold (r = 0.42, P <.01). Exercise capacity was poorly related to occupational and recreational activities when expressed as average weekly energy expended throughout adulthood.Post-CTX patients maintain a moderately active lifestyle. Measures of exercise tolerance generally are related to recent daily recreational activities in CTX patients, but these associations are modest. The many physiologic factors unique to CTX recipients likely play a more important role than deconditioning in determining exercise tolerance in these patients.

    View details for PubMedID 12668931

  • Effects of initiating carvedilol in patients with severe chronic heart failure - Results from the COPERNICUS study JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Krum, H., Roecker, E. B., Mohacsi, P., Rouleau, J. L., Tendera, M., COATS, A. J., Katus, H. A., Fowler, M. B., Packer, M. 2003; 289 (6): 712-718


    Beta-blockers remain underused despite their established utility for improving outcome in heart failure. Concerns that initiation of treatment produces few immediate benefits and may have important risks may be deterring widespread use.To evaluate the early effects of the beta-blocker carvedilol in patients with severe heart failure.Randomized, double-blind, placebo-controlled trial conducted from October 28, 1997, to March 20, 2000, at 334 hospital centers in 21 countries among 2289 patients with symptoms of heart failure at rest or with minimal exertion who were clinically euvolemic and had a left ventricular ejection fraction of less than 25%.Patients were randomly assigned to receive carvedilol, with start dosage of at 3.125 mg twice daily with uptitration to a target dosage of 25 mg twice daily (n = 1156), or placebo (n = 1133), in addition to their usual medications for heart failure.Death, hospitalization, or permanent withdrawal from study drug, as well as adverse events during the first 8 weeks of treatment.The carvedilol group experienced no increase in cardiovascular risk but instead had fewer patients who died (19 vs 25; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.41-1.35); who died or were hospitalized (134 vs 153; HR, 0.85; 95% CI, 0.67-1.07); or who died, were hospitalized, or were permanently withdrawn from treatment (162 vs 188; HR, 0.83; 95% CI, 0.68-1.03). These effects were similar in direction and magnitude to those observed during the entire study, and were apparent particularly in the 624 patients with recent or recurrent decompensation or a very depressed left ventricular ejection fraction. Differences in favor of carvedilol became apparent as early as 14 to 21 days following initiation of treatment. Worsening heart failure was the only serious adverse event with a frequency greater than 2% and was reported with similar frequency in the placebo and carvedilol groups (6.4% vs 5.1%).These data suggest that, in clinically euvolemic patients, the relation of benefit to risk during initiation of treatment with carvedilol is similar to that seen during long-term therapy with the drug. Our findings should provide the reassurance needed to encourage the high levels of use that are warranted by the results of long-term clinical trials.

    View details for Web of Science ID 000180886000025

    View details for PubMedID 12585949

  • Effect of carvedilol on the morbidity of patients with severe chronic heart failure - Results of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study CIRCULATION Packer, M., Fowler, M. B., Roecker, E. B., COATS, A. J., Katus, H. A., Krum, H., Mohacsi, P., Rouleau, J. L., Tendera, M., Staiger, C., Holcslaw, T., Amann-Zalan, I., DeMets, D. L. 2002; 106 (17): 2194-2199


    Beta-blocking agents improve functional status and reduce morbidity in mild-to-moderate heart failure, but it is not known whether they produce such benefits in severe heart failure.We randomly assigned 2289 patients with symptoms of heart failure at rest or on minimal exertion and with an ejection fraction <25% (but not volume-overloaded) to double-blind treatment with either placebo (n=1133) or carvedilol (n=1156) for an average of 10.4 months. Carvedilol reduced the combined risk of death or hospitalization for a cardiovascular reason by 27% (P=0.00002) and the combined risk of death or hospitalization for heart failure by 31% (P=0.000004). Patients in the carvedilol group also spent 27% fewer days in the hospital for any reason (P=0.0005) and 40% fewer days in the hospital for heart failure (P<0.0001). These differences were as a result of both a decrease in the number of hospitalizations and a shorter duration of each admission. More patients felt improved and fewer patients felt worse in the carvedilol group than in the placebo group after 6 months of maintenance therapy (P=0.0009). Carvedilol-treated patients were also less likely than placebo-treated patients to experience a serious adverse event (P=0.002), especially worsening heart failure, sudden death, cardiogenic shock, or ventricular tachycardia.In euvolemic patients with symptoms at rest or on minimal exertion, the addition of carvedilol to conventional therapy ameliorates the severity of heart failure and reduces the risk of clinical deterioration, hospitalization, and other serious adverse clinical events.

    View details for DOI 10.1161/01.CIR.0000035653.72855.BF

    View details for Web of Science ID 000178839800009

    View details for PubMedID 12390947

  • High prevalence of impaired glucose metabolism in patients with idiopathic dilated cardiomyopathy Jamali, A. H., Witteles, R. M., Tang, W. H., Chu, J. W., Reaven, G. M., Fowler, M. B. ELSEVIER SCIENCE INC. 2002: 181A–181A
  • Reverse remodeling following long-term carvedilol therapy is associated with improvement in survival: The Stanford Carvedilol Echocardiographic Registry Tang, W. H., Larson, M. S., Vagelos, R. H., Prikazsky, L., Hu, B. S., Fowler, M. B. ELSEVIER SCIENCE INC. 2002: 141A–141A
  • Neurohormonal and clinical responses to high- versus low-dose enalapril therapy in chronic heart failure JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Tang, W. H., Vagelos, R. H., Yee, Y. G., Benedict, C. R., Willson, K., Liss, C. L., Labelle, P., Fowler, M. B. 2002; 39 (1): 70-78


    We sought to compare the neurohormonal responses and clinical effects of long-term, high-dose versus low-dose enalapril in patients with chronic heart failure (CHF).Examination of neurohormonal and clinical responses in patients receiving different doses of angiotensin-converting enzyme (ACE) inhibitors may provide insight into the potential for additional suppression with angiotensin II (AT-II) or aldosterone antagonists.Seventy-five patients with CHF were randomized to receive either high-dose (40 mg/day, n = 37) or low-dose (5 mg/day, n = 38) enalapril over six months. The results from exercise testing, echocardiography, tissue-specific ACE activity and monthly pre- and post-enalapril neurohormonal levels were compared.Despite greater intra-group improvements in plasma renin activity and serum aldosterone levels in the high-dose group, no statistically significant differences were observed between the two groups in all variables, except for serum ACE activity at the end of study. Elevated serum aldosterone and plasma AT-II levels were observed in 35% and 85% of patients, respectively, at 34 weeks, an inter-group difference that was not statistically significant. A trend toward higher levels of tissue-specific ACE activity in the high-dose group compared with the low-dose group at the end of study was observed (p = 0.054). A predefined composite end point of clinical events had a trend toward better improvement in the high-dose group.This study could not demonstrate a difference between high- and low-dose enalapril in terms of serum aldosterone and plasma AT-II suppression, despite a dose-dependent reduction in serum ACE activity. Even at maximal doses of enalapril, elevated serum aldosterone and plasma AT-II levels were frequently observed.

    View details for Web of Science ID 000173007500011

    View details for PubMedID 11755289

  • Beta-adrenergic blocking drugs in severe heart failure. Reviews in cardiovascular medicine Fowler, M. 2002; 3: S20-6


    Beta-adrenergic blocking drugs have been shown to improve survival and well-being of patients with mild to moderate heart failure. In more advanced heart failure, the relationship between the short-term hemodynamic support afforded by activation of the sympathetic nervous system and the harm that results from excess sympathetic activation is more complex. Not all studies of beta-adrenergic blocking drugs or antiadrenergic therapy have shown benefit. The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial has revealed that the combined nonselective beta-adrenergic and a-adrenergic receptor blocking drug carvedilol produces an important salutary effect on the natural history of advanced heart failure. Mortality was reduced by 35% in the carvedilol group, from an annual (Kaplan-Meier) rate of 18.5% to 11.4%. All-cause hospitalizations were reduced by 20% and hospitalization from heart failure by 33%. Even amongst the subgroups at highest risk, no subpopulation could be identified that did not appear to benefit. The trial supports extending the population of those with chronic heart failure who should be routinely treated with beta-adrenergic blocking drugs (in addition to angiotensin-converting enzyme inhibition therapy) to patients with more advanced disease.

    View details for PubMedID 12447158

  • Coreg (R) Heart Failure Registry (COHERE): Characteristics of participating physicians, their patients, and dose-titration experience. Franciosa, J. A., Abraham, W. T., Fowler, M. B., Gilbert, E. M., Greenberg, B. H., Massie, B. M., Lukas, M. A., Nelson, J. J. LIPPINCOTT WILLIAMS & WILKINS. 2001: 801–
  • Effect of carvedilol on frequency and severity of hospitalization in severe chronic heart failure: Results of the COPERNICUS study Fowler, M. B., O'Connor, C. M., Carson, P., Tendera, M., Katus, H. A., Krum, H., Mohacsi, P., Coats, A. J., Rouleau, J. L., Roecker, E. B., Amann-Zalan, I., Holsclaw, T., Packer, M. LIPPINCOTT WILLIAMS & WILKINS. 2001: 753–54
  • Effect of carvedilol on survival in severe chronic heart failure. NEW ENGLAND JOURNAL OF MEDICINE Packer, M., COATS, A. J., Fowler, M. B., Katus, H. A., Krum, H., Mohacsi, P., Rouleau, J. L., Tendera, M., Castaigne, A., Roecker, E. B., Schultz, M. K., DeMets, D. L. 2001; 344 (22): 1651-1658


    Beta-blocking agents reduce the risk of hospitalization and death in patients with mild-to-moderate heart failure, but little is known about their effects in severe heart failure.We evaluated 2289 patients who had symptoms of heart failure at rest or on minimal exertion, who were clinically euvolemic, and who had an ejection fraction of less than 25 percent. In a double-blind fashion, we randomly assigned 1133 patients to placebo and 1156 patients to treatment with carvedilol for a mean period of 10.4 months, during which standard therapy for heart failure was continued. Patients who required intensive care, had marked fluid retention, or were receiving intravenous vasodilators or positive inotropic drugs were excluded.There were 190 deaths in the placebo group and 130 deaths in the carvedilol group. This difference reflected a 35 percent decrease in the risk of death with carvedilol (95 percent confidence interval, 19 to 48 percent; P=0.00013, unadjusted; P=0.0014, adjusted for interim analyses). A total of 507 patients died or were hospitalized in the placebo group, as compared with 425 in the carvedilol group. This difference reflected a 24 percent decrease in the combined risk of death or hospitalization with carvedilol (95 percent confidence interval, 13 to 33 percent; P<0.001). The favorable effects on both end points were seen consistently in all the subgroups we examined, including patients with a history of recent or recurrent cardiac decompensation. Fewer patients in the carvedilol group than in the placebo group withdrew because of adverse effects or for other reasons (P=0.02).The previously reported benefits of carvedilol with regard to morbidity and mortality in patients with mild-to-moderate heart failure were also apparent in the patients with severe heart failure who were evaluated in this trial.

    View details for Web of Science ID 000168963000001

    View details for PubMedID 11386263

  • Race and the response to adrenergic blockade with carvedilol in patients with chronic heart failure. NEW ENGLAND JOURNAL OF MEDICINE Yancy, C. W., Fowler, M. B., Colucci, W. S., Gilbert, E. M., Bristow, M. R., Cohn, J. N., Lukas, M. A., Young, S. T., Packer, M. 2001; 344 (18): 1358-1365


    The benefits of angiotensin-converting-enzyme inhibitors and beta-blockers may be smaller in black patients than in patients of other races, but it is unknown whether race influences the response to carvedilol in patients with chronic heart failure.In the U.S. Carvedilol Heart Failure Trials Program, 217 black and 877 nonblack patients (in New York Heart Association class II, III, or IV and with a left ventricular ejection fraction of no more than 0.35) were randomly assigned to receive placebo or carvedilol (at doses of 6.25 to 50 mg twice daily) for up to 15 months. The effects of carvedilol on ejection fraction, clinical status, and major clinical events were retrospectively compared between black and nonblack patients.As compared with placebo, carvedilol lowered the risk of death from any cause or hospitalization for any reason by 48 percent in black patients and by 30 percent in nonblack patients. Carvedilol reduced the risk of worsening heart failure (heart failure leading to death, hospitalization, or a sustained increase in medication) by 54 percent in black patients and by 51 percent in nonblack patients. The ratios of the relative risks associated with carvedilol for these two outcome variables in black as compared with nonblack patients were 0.74 (95 percent confidence interval, 0.42 to 1.34) and 0.94 (95 percent confidence interval, 0.43 to 2.05), respectively. Carvedilol also improved functional class, ejection fraction, and the patients' and physicians' global assessments in both the black patients and the nonblack patients. For all these measures of outcome and clinical status, carvedilol was superior to placebo within each racial cohort (P<0.05 in all analyses), and there was no significant interaction between race and treatment (P> 0.05 in all analyses).The benefit of carvedilol was apparent and of similar magnitude in both black and nonblack patients with heart failure.

    View details for Web of Science ID 000168413500003

    View details for PubMedID 11333992

  • Influence of carvedilol on hospitalizations in heart failure: incidence, resource utilization and costs. U.S. Carvedilol Heart Failure Study Group. Journal of the American College of Cardiology Fowler, M. B., Vera-Llonch, M., Oster, G., Bristow, M. R., Cohn, J. N., Colucci, W. S., Gilbert, E. M., Lukas, M. A., Lacey, M. J., Richner, R., Young, S. T., Packer, M. 2001; 37 (6): 1692-1699


    Carvedilol reduces disease progression in heart failure, but to our knowledge, its effects on hospitalizations and costs have not been evaluated.We examined the effects on hospitalization frequency and costs in the U.S. Carvedilol Heart Failure Trials Program. This program consisted of four concurrent, multicenter, double-blind, placebo-controlled studies involving 1,094 patients with New York Heart Association class II to IV heart failure, which treated patients with placebo or carvedilol for up to 15 months (median, 6.5 months).Detailed resource utilization data were collected for all hospitalizations occurring between randomization and the end of follow-up. In-patient care costs were estimated based on observed levels of resource use.Compared with placebo, carvedilol reduced the risk of hospitalization for any reason by 29% (p = 0.009), cardiovascular hospitalizations by 28% (p = 0.034) and heart failure hospitalizations by 38% (p = 0.041). Carvedilol also decreased the mean number of hospitalizations per patient (for cardiovascular reasons 30% [p = 0.02], for heart failure 53% [p = 0.03]). Among hospitalized patients, carvedilol reduced severity of illness during hospital admission, as reflected by shorter length of stay and less frequent use of intensive care. For heart failure hospital admissions, carvedilol decreased mean length of stay by 37% (p = 0.03) and mean number of intensive care unit/coronary care unit days by 83% (p = 0.001), with similar effects on cardiovascular admissions. As a result, estimated inpatient care costs with carvedilol were 57% lower for cardiovascular admissions (p = 0.016) and 81% lower for heart failure admissions (p = 0.022).Carvedilol added to angiotensin-converting enzyme inhibition reduces hospitalization risk as well as severity of illness and resource utilization during admission in patients with chronic heart failure.

    View details for PubMedID 11345386

  • The role of angiotensin receptor blockers in the management of chronic heart failure ARCHIVES OF INTERNAL MEDICINE Jamali, A. H., Tang, W. H., Khot, U. N., Fowler, M. B. 2001; 161 (5): 667-672


    Clinical and basic science research has repeatedly confirmed the importance of the renin-angiotensin-aldosterone system in the pathophysiology of chronic heart failure. Accordingly, blockade of this system by angiotensin-converting enzyme (ACE) inhibitors has assumed a central role in the treatment of heart failure. Recently, angiotensin II receptor blockers (ARBs) have gained prominence as a possible substitute for ACE inhibitors in therapy for heart failure. However, clinical data compiled on this use of ARBs have shown them to be useful only as alternative therapy in ACE inhibitor-intolerant patients. Continuing large-scale clinical investigations may lead to an expansion of their role in therapy for various cardiovascular diseases.

    View details for Web of Science ID 000167339200004

    View details for PubMedID 11231698

  • Rationale, design, and methods for a Coreg (Carvedilol) heart failure registry (COHERE) JOURNAL OF CARDIAC FAILURE Franciosa, J. A., Abraham, W. T., Fowler, M., Gilbert, E. M., Greenberg, B., Massie, B. M., Chen, T., Lukas, M. A., Nelson, J. J. 2000; 6 (3): 264-271


    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.

    View details for Web of Science ID 000089177800013

    View details for PubMedID 10997754

  • Baseline clinical parameters do not predict left ventricular ejection fraction improvement Tang, W. H., Khot, U. N., Larson, M. S., Prikazsky, L., Hu, B. S., Tan, J. L., Fowler, M. B. ELSEVIER SCIENCE INC. 2000: 207A–207A
  • Cardiopulmonary exercise testing and prognosis in severe heart failure: 14 mL/kg/min revisited AMERICAN HEART JOURNAL Myers, J., Gullestad, L., Vagelos, R., Do, D., Bellin, D., Ross, H., Fowler, M. B. 2000; 139 (1): 78-84


    Accurately establishing prognosis in severe heart failure has become increasingly important in assessing the efficacy of treatment modalities and in appropriately allocating scarce resources for transplantation. Peak exercise oxygen uptake appears to have an important role in risk stratification of patients with heart failure, but the optimal cutpoint value to separate survivors from nonsurvivors is not clear.Six hundred forty-four patients referred for heart failure evaluation over a 10-year period participated in the study. After pharmacologic stabilization at entrance into the study, all participants underwent cardiopulmonary exercise testing. Survival analysis was performed with death as the end point. Transplantation was considered a censored event. Four-year survival was determined for patients who achieved peak oxygen uptake values greater than and less than 10, 11, 12, 13, 14, 15, 16, and 17 mL/kg/min.Follow-up information was complete for 98.3% of the cohort. During a mean follow-up period of 4 years, 187 patients (29%) died and 101 underwent transplantation. Actuarial 1- and 5-year survival rates were 90.5% and 73.4%, respectively. Peak ventilatory oxygen uptake (VO(2)) was an independent predictor of survival and was a stronger predictor than work rate achieved and other exercise and clinical variables. A difference in survival of approximately 20% was achieved by dichotomizing patients above versus below each peak VO(2) value ranging between 10 and 17 mL/kg/min. Survival rate was significantly higher among patients achieving a peak VO (2) above than among those achieving a peak VO (2) below each of these values (P <.01), but each cutpoint was similar in its ability to separate survivors from nonsurvivors.Peak VO (2) is an important measurement in predicting survival from heart failure, but whether an optimal cutpoint exists is not clear. Peak VO(2) may be more appropriately used as a continuous variable in multivariate models to predict prognosis in severe chronic heart failure.

    View details for Web of Science ID 000084631300012

    View details for PubMedID 10618566

  • Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Gullestad, L., Aukrust, P., Ueland, T., Espevik, T., Yee, G., Vagelos, R., Froland, S. S., Fowler, M. 1999; 34 (7): 2061-2067


    We examined the effect of long-term treatment with two doses of the angiotensin converting enzyme (ACE) inhibitor enalapril on various immunological variables in patients with chronic congestive heart failure (CHF).Immunological mediators are increasingly recognized to play a pathogenic role in the pathophysiology of CHF. Whether ACE inhibitor therapy modifies immunological variables has not previously been investigated.Seventy-five patients (mean age 52 +/- 11 years) with CHF were randomized between low-(5 m g daily) and high-dose (40 mg daily) enalapril in a double-blind trial. Circulating levels of immunological parameters (i.e., proinflammatory cytokines, chemokines and adhesion molecules) were measured at baseline, at 10 weeks and at the end of the study (34 weeks).All immunological parameters, except soluble interleukin (IL)-6 receptor, were increased in CHF compared with 21 healthy controls. During the study immunoreactive IL-6 levels decreased (p < 0.05) and soluble IL-6 receptor increased (p < 0.05) during high-dose but not during low-dose enalapril therapy. Furthermore, IL-6 bioactivity decreased only during the high-dose (p < 0.001), resulting in a significant difference in change during treatment between the two dosage groups (p < 0.001). This decrease in IL-6 bioactivity was significantly associated with decreased interventricular septum thickness as assessed by echocardiography (r = 0.56, p = 0.013). No other variables changed during treatment.In patients with severe CHF, high-dose enalapril therapy is associated with a significant decrease in IL-6 activity. However, despite treatment with a high-dose ACE inhibitor, a persistent immune activation exists in these patients which may be of importance for the progression of CHF.

    View details for Web of Science ID 000083956400034

    View details for PubMedID 10588224

  • A genetic locus for ventricular arrhythmia and dilated cardiomyopathy on chromosome 2 Dreher, D., Zhu, X. L., Hoang, K. L., Tan, J. L., Vagelos, R. H., Hunt, S. A., Fowler, M. B., McNally, E. M. LIPPINCOTT WILLIAMS & WILKINS. 1999: 217–17
  • The influence of beta-adrenergic blocking drugs on morbidity and mortality in heart failure JOURNAL OF CARDIOVASCULAR RISK Fowler, M. B. 1999; 6 (3): 141-144

    View details for Web of Science ID 000082190200003

    View details for PubMedID 10463139

  • Cost effectiveness of carvedilol for heart failure AMERICAN JOURNAL OF CARDIOLOGY Delea, T. E., Vera-Llonch, M., Richner, R. E., Fowler, M. B., Oster, G. 1999; 83 (6): 890-896


    In this study, we examine the cost effectiveness of carvedilol for the treatment of chronic heart failure (CHF). We use a Markov model to project life expectancy and lifetime medical care costs for a hypothetical cohort of patients with CHF who were assumed alternatively to receive carvedilol plus conventional therapy (digoxin, diuretics, and angiotensin-converting enzyme inhibitors) or conventional therapy alone. Patients on carvedilol were assumed to experience a reduced risk of death and hospitalization for CHF, which is consistent with findings from the US Carvedilol Heart Failure Trials Program. The benefits of carvedilol were projected under 2 alternative scenarios. In the first ("limited benefits"), benefits were conservatively assumed to persist for 6 months, the average duration of follow-up in these clinical trials, and then end abruptly. In the other ("extended benefits"), they were arbitrarily assumed to persist for 6 months and then decline gradually over time, vanishing by the end of 3 years. We estimated our model using data from the US Carvedilol Heart Failure Trials Program and other sources. For patients receiving conventional therapy alone, estimated life expectancy was 6.67 years; corresponding figures for those also receiving carvedilol were 6.98 and 7.62 years under the limited and extended benefits scenarios, respectively. Expected lifetime costs of CHF-related care were estimated to be $28,756 for conventional therapy, and $36,420 and $38,867 for carvedilol (limited and extended benefits, respectively). Cost per life-year saved for carvedilol was $29,477 and $12,799 under limited and extended benefits assumptions, respectively. The cost effectiveness of carvedilol for CHF compares favorably to that of other generally accepted medical interventions, even under conservative assumptions regarding the duration of therapeutic benefit.

    View details for Web of Science ID 000079244000014

    View details for PubMedID 10190405

  • Spontaneous postpartum coronary dissection CIRCULATION Lee, F. H., Yeung, A. C., Fowler, M. B., Fitzgerald, P. J. 1999; 99 (5): 721-721

    View details for Web of Science ID 000078473000020

    View details for PubMedID 9950672

  • beta-blockers in heart failure - Do they improve the quality as well as the quantity of life? Satellite Symposium on Health Economics and Quality of Life Issues in Heart Failure, at the XIXth Congress of the European-Society-of-Cardiology Fowler, M. B. OXFORD UNIV PRESS. 1998: P17–P25


    Heart failure is a common clinical problem in patients with cardiovascular disease. Mortality remains high despite conventional therapy. The morbidity associated with heart failure accounts for numerous hospitalizations and significant health care expenditures. Therapy has been directed at relieving symptoms, augmenting exercise capacity, reducing hospitalizations and improving survival. Randomized clinical trials have shown that angiotensin-converting enzyme (ACE) inhibitors achieve these therapeutic goals and exert a favourable influence on disease progression. Recent clinical trials evaluating metoprolol, bisoprolol and carvedilol have clearly established that judicious use of beta-adrenergic blockers in heart failure patients who have been stabilized favourably influences the natural history of the disease, even when given as additional therapy to patients already receiving ACE inhibitors. Carvedilol is a non-selective beta-adrenergic blocking drug with vasodilatory properties that has been recently approved by the U.S. Food and Drug Administration for use in patients with NYHA functional class II or III heart failure. It was the only agent to produce a statistically significant survival benefit in a pre-specified analysis that included all the patients randomized into the multicentre U.S. Carvedilol Heart Failure Trials Program, irrespective of disease aetiology. As with trials looking at ACE inhibitor therapy, studies involving beta-blocker therapy in patients with heart failure have evaluated the effects of these drugs on hospitalization, NYHA functional class, exercise capacity and survival. In the U.S. Carvedilol Heart Failure Trials Program, the risk of hospitalization for any cause was reduced by 29%, the risk of hospitalization for a cardiovascular cause was reduced by 28% and the risk of dying was reduced by 65%. Thus, carvedilol has been shown in randomized clinical trials to improve the quantity of life and, at least in terms of the incidence of hospitalization, to improve the qualify of life as well. Randomized trials have consistently reported a favourable change in NYHA functional class in patients treated with beta-adrenergic blocking drugs: the majority of patients became less symptomatic. In the U.S. Carvedilol trials, patients and physicians reported (separately) an improvement in global status, and less deterioration when treatment was randomized to carvedilol. The positive influence of such therapy is reflected in a reduction in hospitalizations. In summary, patients with NYHA class II or III who have been stabilized with ACE inhibitors and diuretics can expect an improvement in the quality as well as the quantity of life with beta-blocker therapy.

    View details for Web of Science ID 000077571800005

    View details for PubMedID 9886708

  • Relationship between tissue and circulating levels of angiotensin converting enzyme with high and low dose enalapril therapy in heart failure Fowler, M. B., Yee, Y. G., Vagelos, R. H., Willson, K., Prikazsky, L., Mullin, A., Waldman-Boucher, M. LIPPINCOTT WILLIAMS & WILKINS. 1998: 854–54
  • Clinical, hemodynamic, and cardiopulmonary exercise test determinants of survival in patients referred for evaluation of heart failure ANNALS OF INTERNAL MEDICINE Myers, J., Gullestad, L., Vagelos, R., Do, D., Bellin, D., Ross, H., Fowler, M. B. 1998; 129 (4): 286-?


    Accurate prognosis in chronic heart failure has become increasingly important in assessing the efficacy of treatment and in appropriately allocating scarce resources for transplantation. Previous studies of severe heart failure have been limited by short follow-up periods and few deaths.To establish clinical, hemodynamic, and cardiopulmonary exercise test determinants of survival in patients with heart failure.Retrospective study.Hospital-based outpatient heart failure clinic.644 patients referred for evaluation of heart failure over 10 years.Age, cause of heart failure, body surface area, cardiac index, ejection fraction, pulmonary capillary wedge pressure, left ventricular dimensions, watts achieved during exercise, heart rate, maximum systolic blood pressure, and oxygen uptake (VO2) at the ventilatory threshold and at peak exercise were measured at baseline. Univariate and multivariate analyses were done for clinical, hemodynamic, and exercise test predictors of death. A Cox hazards model was developed for time of death.During a mean follow-up period of 4 years, 187 patients (29%) died and 101 underwent transplantation. Actuarial 1-year and 5-year survival rates were 90.5% and 73.4%, respectively. Resting systolic blood pressure, watts achieved, peak VO2, VO2 at the ventilatory threshold, and peak heart rate were greater among survivors than among nonsurvivors. Cause of heart failure (coronary artery disease or cardiomyopathy) was a strong determinant of death (relative risk for coronary artery disease, 1.73; P< 0.01). By multivariate analysis, only peak VO2 was a significant predictor of death. Stratification of peak VO2 above and below 12, 14, and 16 mL/kg per minute demonstrated significant differences in risk for death, but each cut-point predicted risk to a similar degree.Peak VO2 outperforms clinical variables, right-heart catheterization data, exercise time, and other exercise test variables in predicting outcome in severe chronic heart failure. Direct measurement of VO2 should be included when clinical or surgical decisions are being made in patients referred for evaluation of heart failure or those considered for transplantation.

    View details for Web of Science ID 000075329100004

    View details for PubMedID 9729181

  • Neuropeptide Y receptor 1 (NPY-Y1) expression in human heart failure and heart transplantation JOURNAL OF THE AUTONOMIC NERVOUS SYSTEM Gullestad, L., Aass, H., Ross, H., Ueland, T., Geiran, O., KJEKSHUS, J., Simonsen, S., Fowler, M., Kobilka, B. 1998; 70 (1-2): 84-91


    Neuropeptide Y (NPY) is a neurotransmitter released from cardiac sympathetic nerve terminals along with catecholamines. It influences vascular tone and cardiac function, probably through the receptor subtype Y1. The present study examined the expression of Y1 in patients with end-stage heart failure and in heart transplant recipients. Y1 mRNA was analyzed in right ventricular endomyocardial biopsies taken from 12 donor hearts prior to implantation (controls), 15 patients with end stage heart failure at time of transplantation, and 16 patients more than 1 year after transplantation. RT-PCR (reverse transcription polymerase chain reaction) was used to detect mRNA for the Y1 receptor, the beta1-adrenergic-receptor, and beta-actin. Y1 mRNA was present in biopsies of all donor hearts, but was observed significantly less frequently in the two patient groups; only 5 out of 15 (P < 0.01) heart failure and 9 out of 16 (P < 0.05) transplant recipients demonstrated visible PCR product. In contrast, mRNA for the beta1-adrenergic receptor and beta-actin were detected by RT-PCR in all samples. Our results provide the first evidence for altered regulation of the neuropeptide Y1 receptor in heart failure and transplant patients, and suggests that loss of signal transduction by this receptor may be adaptive in both groups.

    View details for Web of Science ID 000074669200012

    View details for PubMedID 9686908

  • Angiotensin II receptor subtype AT(1) and AT(2) expression after heart transplantation CARDIOVASCULAR RESEARCH Gullestad, L., Haywood, G., Aass, H., Ross, H., Yee, G., Ueland, T., Geiran, O., KJEKSHUS, J., Simonsen, S., Bishopric, N., Fowler, M. 1998; 38 (2): 340-347


    Cardiac hypertrophy appears early after heart transplantation, and may represent a myocardial response to injury. Recent evidence suggests that angiotensin II (Ang II) may promote growth through the AT1 and inhibit growth through the AT2 receptor subtypes. We therefore asked whether hypertrophy after heart transplantation is characterized by alterations in Ang II receptor gene expression.The expression of Ang II receptor subtypes. AT1 and AT2, was analyzed in right ventricular endomyocardial biopsies taken from 10 human donor hearts prior to implantation (controls) and from 17 heart transplant recipients, 11 studied during annual evaluation (> 1 year after transplantation) and 6 one week after transplantation. Competitive reverse transcription polymerase chain reaction (RT-PCR) was performed using synthetic RNA internal standards for both receptor subtypes.AT1 and AT2 receptor mRNAs were detected in all samples. AT1 receptor mRNA decreased 4.5 fold (p < 0.01) and AT2 receptor mRNA 4.2 fold (p < 0.001) in transplant patients compared with controls. In the subgroup of patients examined one week after surgery AT1 was reduced relative to AT2 receptor mRNA, resulting in an altered ratio of AT1 to AT2 early after transplantation. There was no correlation between Ang II receptor levels and left ventricular wall thickness, and the decrease in receptor level did not correlate with any hemodynamic parameters, cyclosporine blood levels, or plasma renin, Ang II or pANP, except for a negative correlation between AT2 mRNA and plasma renin (r = -0.49, p = 0.05).Contrary to our expectations, mRNA for both Ang II receptors was downregulated after heart transplantation. The cause of myocardial hypertrophy after heart transplantation is still unclear, but the hypertrophy does not appear to be driven by increased transcription of the AT1 receptor.

    View details for Web of Science ID 000074585800007

    View details for PubMedID 9709394

  • Use of assumed versus measured oxygen consumption for the determination of cardiac output using the Fick principle CATHETERIZATION AND CARDIOVASCULAR DIAGNOSIS Wolf, A., Pollman, M. J., Trindade, P. T., Fowler, M. B., Alderman, E. L. 1998; 43 (4): 372-380


    Assumed oxygen consumption (VO2) is increasingly used as a convenient surrogate for measured VO2 for calculation of cardiac output. This substitution is often based on empirical formulae, previously validated only in relatively young patients. To assess the inaccuracy introduced by extrapolating these formulae to older patients, we compared measured VO2 with assumed VO2 in 57 patients. VO2 was measured using an open circuit analyzer. Assumed VO2 was calculated according to the LaFarge or Bergstra formulae. Agreement between both methods was assessed according to the method of Bland and Altman. The mean difference of measured VO2 minus assumed VO2 was 7.9 ml/min/m2 (P < 0.02) using the LaFarge formula, and -15.6 ml/min/m2 (P < 0.0002) using the Bergstra formula across a range of measured VO2 from 70 to 176 ml/min/m2. A systematic error was introduced by assumed VO2 from both formulae of underestimating higher and overestimating lower values of VO2, resulting in poor overall agreement with measured VO2. The same error and poor agreement was found when analyzing subgroups of patients > or =60 or <70 years of age. In summary, use of assumed VO2 introduces large, unpredictable errors in adult patients, suggesting requirement for measurement of VO2 when calculating cardiac output.

    View details for Web of Science ID 000072785800003

    View details for PubMedID 9554760

  • Serial exercise testing and prognosis in selected patients considered for cardiac transplantation AMERICAN HEART JOURNAL Gullestad, L., Myers, J., Ross, H., Rickenbacher, P., Slauson, S., Bellin, D., Vagelos, R., Fowler, M. 1998; 135 (2): 221-229


    This study sought to examine the predictive value of variables obtained from serial maximal exercise testing, echocardiography, and ejection fraction in patients referred as potential heart transplant candidates.Variables such as peak VO2, left ventricular dimensions, ejection fraction, and hemodynamic measurements are known to predict prognosis in heart failure, but there are few data on the impact of serial measurements of these variables on subsequent mortality.Two hundred sixty-three ambulatory patients with severe heart failure referred as potential candidates for heart transplantation who underwent two exercise tests (mean 7.8 months apart) after optimal medical treatment were identified. At the same two time points, echocardiography was performed in 106 (37%) and ejection fraction was measured in 84 (30%). During a mean follow-up period of 3.9+/-0.1 years, 70 (25%) died and 45 (19%) underwent heart transplantation. Exercise capacity, peak exercise heart rate, and peak exercise systolic blood pressure achieved were all significantly higher among survivors compared with nonsurvivors. Among the survivors a slight increase in peak VO2 and ejection fraction were observed, but there were no significant differences in the changes of any of the measured variables between survivors and nonsurvivors. There were no significant differences in survival between patients with increased versus those with decreased peak VO2, left ventricular dimensions, or ejection fraction.Although peak VO2, left ventricular dimensions, and ejection fraction predict survival, changes in these parameters do not add any prognostic information in patients with severe heart failure who have been stabilized with optimal medical treatment. Routine use of these procedures therefore does not seem to be warranted and should be performed only in the context of a specific clinical situation. Serial measurements of these parameters do not appear to be useful in the risk stratification of patients referred for heart transplantation.

    View details for Web of Science ID 000072129400006

    View details for PubMedID 9489968

  • Effects of beta blockers on symptoms and functional capacity in heart failure. American journal of cardiology Fowler, M. B. 1997; 80 (11A): 55L-58L


    Beta-adrenergic-blocking drugs ameliorate the progression of disease that usually characterizes heart failure. All of the larger multicenter studies have demonstrated reductions in morbidity, manifested by a reduction in the number of hospitalizations and/or listing for cardiac transplantation, whereas studies with carvedilol have also reported a significant reduction in mortality. The influence of beta-adrenergic blocking drugs on the symptomatic and functional status of patients with heart failure has been more difficult to establish. Almost all trials have reported an improvement in New York Heart Association (NYHA) functional class, with few patients experiencing functional deterioration. Improvement in symptom score was reported in the Metoprolol in Dilated Cardiomyopathy (MDC) trial far patients treated with metoprolol. In patients from the US Carvedilol Heart Failure Trials Program who had heart failure from ischemic and nonischemic etiologies, both patients and physicians reported more improvement and less deterioration in an assessment of global status. More formal instruments to assess quality of life, such as the specific activity scale in the Australia-New Zealand trial of carvedilol (that recruited 30% of patients who bad improved to NYHA stage I) and the Minnesota Quality of Life questionnaire, did not seem sensitive to the clinical benefits observed in these trials. Serial exercise testing similarly does not seem sensitive to the beneficial influence of beta-adrenergic blocking drugs on disease progression, at least in relatively short-term studies.

    View details for PubMedID 9412543

  • Comparison of high versus low dose enalapril therapy on clinical outcomes and neuroendocrine activation in advanced heart failure Fowler, M. B., Vagelos, R. H., Schroeder, J. S., Benedict, C. R., Willson, K., Boucher, M., Mullin, A., Prikazsky, L. M., Liss, C. L., Labelle, P. LIPPINCOTT WILLIAMS & WILKINS. 1997: 105–
  • Assessment of left ventricular wall motion abnormalities with the use of color kinesis: A valuable visual and training aid JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Lau, Y. S., Puryear, J. V., Gan, S. C., Fowler, M. B., Vagelos, R. H., Popp, R. L., Schnittger, I. 1997; 10 (6): 665-672


    Accurate interpretation of left ventricular segmental wall motion by echocardiography is an important yet difficult skill to learn. Color-coded left ventricular wall motion (color kinesis) is a tool that potentially could aid in the interpretation and provide semiquantification. We studied the usefulness of color kinesis in 42 patients with a history of congestive cardiomyopathy who underwent two-dimensional echocardiograms and a color kinesis study. The expert's reading of the two-dimensional wall motion served as a reference for comparison of color kinesis studies interpreted by the expert and a cardiovascular trainee. Correlation between two-dimensional echocardiography and the expert's and trainee's color coded wall motion scores were r = 0.83 and r = 0.67, respectively. Reproducibility between reviewers and between operators was also assessed. Interobserver variability for color-coded wall motion showed a correlation of r = 0.78. Correlation between operators was also good; r = 0.84. Color kinesis is reliable and appears promising as an adjunct in the assessment of wall motion abnormalities by echocardiography. It is both a valuable visual aid, as well as a training aid for the cardiovascular trainee.

    View details for Web of Science ID A1997XR35200011

    View details for PubMedID 9282356

  • AT(1) and AT(2) angiotensin receptor gene expression in human heart failure CIRCULATION Haywood, G. A., Gullestad, L., Katsuya, T., Hutchinson, H. G., Pratt, R. E., Horiuchi, M., Fowler, M. B. 1997; 95 (5): 1201-1206


    The availability of selective antagonists for angiotensin II receptors has focused interest on the gene expression of angiotensin II-receptor subtypes in the human heart.We analyzed expression of the AT1 and AT2 subtypes of the angiotensin II receptor in ventricular myocardium taken from 9 donor hearts before implantation and from 12 patients with heart failure (6 with dilated cardiomyopathy and 6 with ischemic heart disease). Competitive reverse transcription-polymerase chain reaction with synthetic RNA internal standards was used to detect mRNA for both subtypes and to quantify relative differences in levels between failing and non-failing ventricular myocardium. AT1- and AT2-receptor mRNA could be detected in all samples. AT1-receptor gene expression was 2.5-fold greater in nonfailing hearts than in patients with failing hearts (P = .015). There was no significant difference in AT2-receptor mRNA expression in failing and nonfailing hearts.The level of expression of the angiotensin AT1 receptor appears to decrease in the failing human ventricle whereas the level of AT2 expression is unaffected. These changes parallel the changes found in human ventricular myocardium at the receptor level, suggesting that the changes in receptor level may result from changes in gene expression or mRNA stability.

    View details for Web of Science ID A1997WK42100020

    View details for PubMedID 9054850

  • A comprehensive management system for heart failure improves clinical outcomes and reduces medical resource utilization AMERICAN JOURNAL OF CARDIOLOGY West, J. A., Miller, N. H., Parker, K. M., Senneca, D., Ghandour, G., Clark, M., Greenwald, G., Heller, R. S., Fowler, M. B., DeBusk, R. F. 1997; 79 (1): 58-63


    The effectiveness of heart failure management in clinical practice is limited by physicians' suboptimal utilization of effective medications, patients' poor adherence to dietary sodium limitation and optimal drug therapy, and the lack of systematic monitoring of patients after hospitalization. The present study evaluated the feasibility and safety of MULTIFIT, a physician-supervised, nurse-mediated, home-based system for heart failure management that implements consensus guidelines for pharmacologic and dietary therapy using a nurse manager to enhance dietary and pharmacologic adherence and to monitor clinical status by frequent telephone contact. Fifty-one patients with the clinical diagnosis of heart failure were followed for 138 +/- 44 days. Daily dietary sodium intake fell by 38%, from 3,393 to 2,088 mg (p = 0.0001); average daily medication doses increased significantly (lisinopril: 17 to 23 mg, p <0.001; hydralazine: 140 to 252 mg, p = 0.01). Functional status and exercise capacity improved significantly (p = 0.01). Compared with the 6 months before enrollment and normalized for variable follow-up, the frequency of general medical and cardiology visits declined by 23% and 31%, respectively (both p <0.03); emergency room visits for heart failure and for all causes declined 67% and 53%, respectively (both p <0.001). Hospitalization rates for heart failure and for all causes declined 87% and 74%, respectively (p = 0.001), compared with the year before enrollment. The MULTIFIT system enhanced the effectiveness of pharmacologic and dietary therapy for heart failure in clinical practice, improving clinical outcomes and reducing medical resource utilization.

    View details for Web of Science ID A1997WB84200012

    View details for PubMedID 9024737

  • Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure CIRCULATION Bristow, M. R., Gilbert, E. M., Abraham, W. T., Adams, K. F., Fowler, M. B., Hershberger, R. E., Kubo, S. H., Narahara, K. A., INGERSOLL, H., Krueger, S., Young, S., Shusterman, N. 1996; 94 (11): 2807-2816


    We conducted a multicenter, placebo-controlled trial designed to establish the efficacy and safety of carvedilol, a "third-generation" beta -blocking agent with vasodilator properties, in chronic heart failure.Three hundred forty-five subjects with mild to moderate, stable chronic heart failure were randomized to receive treatment with placebo, 6.25 mg BID carvedilol (low-dose group), 12.5 mg BID carvedilol (medium-dose group), or 25 mg BID carvedilol (high-dose group). After a 2- to 4-week up-titration period, subjects remained on study medication for a period of 6 months. The primary efficacy parameter was submaximal exercise measured by two different techniques, the 6-minute corridor walk test and the 9-minute self-powered treadmill test. Carvedilol had no detectable effect on submaximal exercise as measured by either technique. However, carvedilol was associated with dose-related improvements in LV function (by 5, 6, and 8 ejection fraction [EF] units in the low-, medium-, and high-dose carvedilol groups, respectively, compared with 2 EF units with placebo, P < .001 for linear dose response) and survival (respective crude mortality rates of 6.0%, 6.7%, and 1.1% with increasing doses of carvedilol compared with 15.5% in the placebo group, P < .001). When the three carvedilol groups were combined, the all-cause actuarial mortality risk was lowered by 73% in carvedilol-treated subjects (P < .001). Carvedilol also lowered the hospitalization rate (by 58% to 64%, P = .01) and was generally well tolerated.In subjects with mild to moderate heart failure from systolic dysfunction, carvedilol produced dose-related improvements in LV function and dose-related reductions in mortality and hospitalization rate.

    View details for Web of Science ID A1996VV27400023

    View details for PubMedID 8941106

  • Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure CIRCULATION Colucci, W. S., Packer, M., Bristow, M. R., Gilbert, E. M., Cohn, J. N., Fowler, M. B., Krueger, S. K., Hershberger, R., Uretsky, B. F., Bowers, J. A., SACKNERBERNSTEIN, J. D., Young, S. T., Holcslaw, T. L., Lukas, M. A. 1996; 94 (11): 2800-2806


    We tested the hypothesis that carvedilol inhibits clinical progression in patients with mildly symptomatic heart failure due to left ventricular (LV) systolic dysfunction.Patients (n = 366) who had mildly symptomatic heart failure with an LV ejection fraction (LVEF) < or = 0.35, had minimal functional impairment (defined as the ability to walk 450 to 550 m on a 6-minute walk test), and were receiving optimal standard therapy, including ACE inhibitors, were randomized double-blind to carvedilol (n = 232) or placebo (n = 134) and followed up for 12 months. The primary end point was clinical progression, defined as death due to heart failure, hospitalization for heart failure, or a sustained increase in heart failure medications. Clinical progression of heart failure occurred in 21% of placebo patients and 11% of carvedilol patients, reflecting a 48% (P = .008) reduction in the primary end point of heart failure progression (relative risk, 0.52; CI, 0.32 to 0.85). This effect of carvedilol was not influenced by sex, age, race, cause of heart failure, or baseline LVEF. Carvedilol also significantly improved several secondary end points, including LVEF, heart failure score, NYHA functional class, and the physician and patient global assessments. Carvedilol reduced all-cause mortality but had no effects on the Minnesota Living With Heart Failure scale, the distance walked in 9 minutes on a self-powered treadmill, or cardiothoracic index. The drug was well tolerated.Carvedilol, when added to standard therapy, including an ACE inhibitor, reduces clinical progression in patients who are only mildly symptomatic with well-compensated heart failure.

    View details for Web of Science ID A1996VV27400022

    View details for PubMedID 8941105

  • Exercise capacity of heart transplant recipients: The importance of chronotropic incompetence JOURNAL OF HEART AND LUNG TRANSPLANTATION Gullestad, L., Haywood, G., Ross, H., Bjornerheim, R., Geiran, O., KJEKSHUS, J., Simonsen, S., Fowler, M. 1996; 15 (11): 1075-1083


    Maximal exercise capacity is limited in patients after heart transplantation. The extent to which chronotropic incompetence contributes to this intolerance has not been well defined.This prospective cross-sectional study examined the heart rate response to exercise and its relation to exercise capacity in 159 heart transplant recipients during progressive, symptom-limited, upright exercise. All prior exercise studies of heart transplant recipients that reported peak oxygen uptake and peak heart rate were also evaluated.Peak oxygen uptake was closely correlated with peak heart rate (r = 0.39, p < 0.001) and maximum increase in heart rate (r = 0.49, p < 0.001) during exercise by our patients. Similar correlations were found in the published studies for peak oxygen uptake versus maximal heart rate (r = 0.54, p < 0.05) and peak oxygen uptake versus increase in heart rate (r = 0.63, p < 0.02). The current study showed that the increase in heart rate from rest to peak exercise was significantly higher and the decline in heart rate after exercise significantly faster for patients 2 or more years after transplantation than for patients less than 2 years after transplantation (46 +/- 2 versus 38 +/- 1.9 beats/min, p < 0.05); the decline in heart rate 4 minutes after exercise was 27 +/- 1.8 versus 16 +/- 1.8 beats/min, respectively ( p < 0.001).The reduction in peak oxygen consumption, particularly during the first 2 years, appears to be related in part to chronotropic incompetence. Late after transplantation the heart rate response to exercise is greater and the decline in heart rate after exercise faster, suggesting possible autonomic reinnervation in some patients. Chronotropic incompetence may be an inadequate explanation of oxygen uptake impairment seen late after transplantation, when other factors such as myocardial dysfunction and intrinsic skeletal muscle abnormalities are of increasing importance.

    View details for Web of Science ID A1996VW83300003

    View details for PubMedID 8956116

  • Effect of carvedilol on survival and hospitalization in patients with ischemic or nonischemic cardiomyopathy Bristow, M. R., Colucci, W. S., Fowler, M. B., Gilbert, E. M., Lukas, M. A., Young, S. T., Hirshberger, R., Adams, K., Kreuger, S., MELMAN, H., Liang, C. S. LIPPINCOTT WILLIAMS & WILKINS. 1996: 1968–68
  • The effect of carvedilol on morbidity and mortality in patients with chronic heart failure NEW ENGLAND JOURNAL OF MEDICINE Packer, M., Bristow, M. R., Cohn, J. N., Colucci, W. S., Fowler, M. B., Gilbert, E. M., Shusterman, N. H. 1996; 334 (21): 1349-1355


    Controlled clinical trials have shown that beta-blockers can produce hemodynamic and symptomatic improvement in chronic heart failure, but the effect of these drugs on survival has not been determined.We enrolled 1094 patients with chronic heart failure in a double-blind, placebo-controlled, stratified program, in which patients were assigned to one of the four treatment protocols on the basis of their exercise capacity. Within each of the four protocols patients with mild, moderate, or severe heart failure with left ventricular ejection fractions < or = 0.35 were randomly assigned to receive either placebo (n = 398) or the beta-blocker carvedilol (n = 696); background therapy with digoxin, diuretics, and an angiotensin-converting-enzyme inhibitor remained constant. Patient were observed for the occurrence death or hospitalization for cardiovascular reasons during the following 6 months, after the beginning (12 months for the group with mild heart failure).The overall mortality rate was 7.8 percent in the placebo group and 3.2 percent in the carvedilol group; the reduction in risk attributable to carvedilol was 65 percent (95 percent confidence interval, 39 to 80 percent; P < 0.001). This finding led the Data and Safety Monitoring Board to recommend termination of the study before its scheduled completion. In addition, as compared with placebo, carvedilol therapy was accompanied by a 27 percent reduction in the risk of hospitalization for cardiovascular causes (19.6 percent vs. 14.1 percent, P = 0.036), as well as a 38 percent reduction in the combined risk of hospitalization or death (24.6 percent vs, 15.8 percent, P < 0.001). Worsening heart failure as an adverse reaction during treatment was less frequent in the carvedilol than in the placebo group.Carvedilol reduces the risk or death as well as the risk of hospitalization for cardiovascular causes in patients with heart failure who are receiving treatment with digoxin, diuretics, and an angiotensin-converting-enzyme inhibitor.

    View details for Web of Science ID A1996UL25100001

    View details for PubMedID 8614419

  • Analysis of deaths in patients awaiting heart transplantation: Impact on patient selection criteria HEART Haywood, G. A., Rickenbacher, P. R., Trindade, P. T., Gullestad, L., Jiang, J. P., Schroeder, J. S., Vagelos, R., Oyer, P., Fowler, M. B. 1996; 75 (5): 455-462


    To analyse the clinical characteristics of patients who died on the Stanford heart transplant waiting list and to develop a method for risk stratifying status 2 patients (outpatients).Data were reviewed from all patients over 18 years, excluding retransplants, who were accepted for heart transplantation over an eight year period from 1986 to 1994.548 patients were accepted for heart transplantation; 53 died on the waiting list, and 52 survived on the waiting list for over one year. On multivariate analysis only peak oxygen consumption (peak VO2: 11.7 (SD 2.7) v 15.1 (5.2) ml/kg/min, P = 0.02) and cardiac output (3.97 (1.03) v 4.79 (1.06) litres/min, P = 0.04) were found to be independent prognostic risk factors. Peak VO2 and cardiac index (CI) were then analysed in the last 141 consecutive patients accepted for cardiac transplantation. All deaths and 88% of the deteriorations to status 1 on the waiting list occurred in patients with either a CI < 2.0 or a VO2 < 12. In those with a CI < 2.0 and a VO2 < 12, 38% died or deteriorated to status 1 in the first year on the waiting list. Patients with CI > or = 2.0 and a VO2 > or = 12 all survived throughout follow up. Using a Cox's proportional hazards model with CI and peak VO2 as covariates, tables were constructed predicting the chance of surviving for (a) 60 days and (b) 1 year on the waiting list.These data provide a basis for risk stratification of status 2 patients on the heart transplant waiting list.

    View details for Web of Science ID A1996UK45400010

    View details for PubMedID 8665337

  • Transplant candidates with severe left ventricular dysfunction managed with medical treatment: Characteristics and survival JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Rickenbacher, P. R., Trindade, P. T., Haywood, G. A., Vagelos, R. H., Schroeder, J. S., Willson, K., Prikazsky, L., Fowler, M. B. 1996; 27 (5): 1192-1197


    This study sought to assess the clinical characteristics and survival of patients with symptomatic heart failure who were referred as potential heart transplant candidates, but were selected for medical management.Patients with severe left ventricular dysfunction referred for heart transplantation may be considered too well to be placed immediately on an active waiting transplant list. The clinical characteristics of this patient group and their survival have not been well defined. These patients represent a unique group that are characterized by comparatively low age and freedom from significant comorbid conditions.We studied 116 consecutive patients with symptomatic heart failure, severe left ventricular dysfunction (left ventricular ejection fraction 20 +/- 7% [mean +/- SD]) and duration of symptoms >1 month referred for heart transplantation, who were acceptable candidates for the procedure but who were not listed for transplantation because of relative clinical stability. These patients were followed up closely on optimal medical therapy. A variety of baseline clinical, hemodynamic and exercise variables were assessed to define this patient group and used to predict cardiac death and requirement later for heart transplantation.During a mean follow-up period of 25.0 +/- 14.8 months (follow-up 99% complete), there were eight cardiac deaths (7%) (seven sudden, one acute myocardial infarction). Only nine patients (8%) were listed for heart transplantation. Actuarial 1- and 4-year cardiac survival rates were 98 +/- 1% and 84 +/- 7% (mean +/- SE), respectively, and freedom from listing for transplantation was 95 +/- 2% and 84 +/- 7% (mean +/- SE), respectively. Patients were mainly in New York Heart Association functional class II or III and had a preserved cardiac index (2.4 liters/min.m2), pulmonary capillary wedge pressure of 16 +/- 9 mm Hg (mean +/- SD) and maximal oxygen consumption of 17.4 +/- 4.3 ml/min per kg (mean +/- SD). By logistic regression analysis, there was no predictor for cardiac death. Longer duration of heart failure (p = 0.013) and mean pulmonary artery (p < 0.05) and pulmonary systolic (p = 0.014) and diastolic (p < 0.05) pressures correlated significantly with listing for heart transplantation by univariate logistic regression. By multivariate logistic regression, only pulmonary artery systolic pressure (p < 0.004) and duration of heart failure (p < 0.015) remained as predictors for need for later transplantation.In the current treatment era, prognosis is favorable in a definable group of transplant candidates despite severe left ventricular dysfunction. This patient group can be identified after intensive medical therapy by stable symptoms, a relatively high maximal oxygen uptake at peak exercise and a preserved cardiac output.

    View details for Web of Science ID A1996UD65100031

    View details for PubMedID 8609341

  • Expression of inducible nitric oxide synthase fin human heart failure CIRCULATION Haywood, G. A., Tsao, P. S., VONDERLEYEN, H. E., Mann, M. J., Kelling, P. J., Trindade, P. T., Lewis, N. P., Byrne, C. D., Rickenbacher, P. R., Bishopric, N. H., Cooke, J. P., McKenna, W. J., Fowler, M. B. 1996; 93 (6): 1087-1094


    There is increasing evidence that alterations in nitric oxide synthesis are of pathophysiological importance in heart failure. A number of studies have shown altered nitric oxide production by the endothelial constitutive isoform of nitric oxide synthase (NOS), but there is very little information on the role of the inducible isoform.We analyzed inducible NOS (iNOS) expression in ventricular myocardium taken from 11 control subjects (who had died suddenly from noncardiac causes), from 10 donor hearts before implantation, and from 51 patients with heart failure (24 with dilated cardiomyopathy [DCM], 17 with ischemic heart disease [IHD], and 10 with valvular heart disease [VHD]). Reverse transcription-polymerase chain reaction was used to confirm the presence of intact mRNA and to detect expression of iNOS and atrial natriuretic peptide (ANP). ANP was used as a molecular phenotypic marker of ventricular failure. iNOS was expressed in 36 of 51 biopsies (71%) from patients with heart failure and in none of the control patients (P<.0001). iNOS expression could also be detected in 50% of the donor hearts. All samples that expressed iNOS also expressed ANP. iNOS gene expression occurred in 67% of patients with DCM, 59% of patients with IHD, and 100% of patients with VHD. To determine whether iNOS protein was expressed in failing ventricles, immunohistochemistry was performed on three donor hearts and nine failing hearts with iNOS mRNA expression. Staining for iNOS was almost undetectable in the donor myocardium and in control sections, but all failing hearts showed diffuse cytoplasmic staining in cardiac myocytes. Expression of iNOS could be observed in all four chambers. Western blot analysis with the same primary antibody showed a specific positive band for iNOS protein in the heart failure specimens; minimal iNOS protein expression was seen in donor heart samples.iNOS expression occurs in failing human cardiac myocytes and may be involved in the pathophysiology of DCM, IHD, and VHD.

    View details for Web of Science ID A1996UA05300006

    View details for PubMedID 8653828

  • Induction of nitric oxide synthase in the human cardiac allograft is associated with contractile dysfunction of the left ventricle CIRCULATION Lewis, N. P., Tsao, P. S., Rickenbacher, P. R., Xue, C., Johns, R. A., Haywood, G. A., VONDERLEYEN, H., Trindade, P. T., Cooke, J. P., Hunt, S. A., Billingham, M. E., Valantine, H. A., Fowler, M. B. 1996; 93 (4): 720-729


    The mechanisms underlying cardiac contractile dysfunction after transplantation remain poorly defined. Previous work has revealed that inducible nitric oxide synthase (iNOS) is expressed in the rat heterotopic cardiac allograft during rejection; resultant overproduction of nitric oxide (NO) might cause cardiac contractile dysfunction via the negative inotropic and cytotoxic actions of NO. In this investigation, we tested the hypothesis that induction of iNOS may occur and be associated with cardiac allograft contractile dysfunction in humans.We prospectively studied 16 patients in the first year after cardiac transplantation at the time of serial surveillance endomyocardial biopsy. Clinical data, the results of biopsy histology, and echocardiographic and Doppler evaluation of left ventricular systolic and diastolic function were recorded. Total RNA was extracted from biopsy specimens, and mRNA for beta-actin, detected by reverse transcription-polymerase chain reaction (RT-PCR) using human specific primers, was used as a constitutive gene control; iNOS mRNA was similarly detected by RT-PCR using human specific primers. iNOS protein was detected in biopsy frozen sections by immunofluorescence. Myocardial cGMP was measured by radioimmunoassay, and serum nitrogen oxide levels (NOx = NO2 + NO3) were measured by chemiluminescence. iNOS mRNA was detected in allograft myocardium at some point in each patient and in 59 of 123 biopsies (48%) overall. In individual patients, iNOS mRNA expression was episodic and time dependent; the frequency of expression was highest during the first 180 days after transplant (P = .0006). iNOS protein associated with iNOS mRNA was detected by immunofluorescence in cardiac myocytes. iNOS mRNA expression was not related to the ISHLT histological grade of rejection or to serum levels of NOx but was associated with increased levels of myocardial cGMP (P = .01) and with both systolic (P = .024) and diastolic (P = .006) left ventricular contractile dysfunction measured by echocardiography and Doppler.These data support a relation between iNOS mRNA expression and contractile dysfunction in the human cardiac allograft.

    View details for Web of Science ID A1996TV05300015

    View details for PubMedID 8641001

  • The relationship of granzyme A and perforin expression to cardiac allograft rejection and dysfunction 14th Annual Meeting of the American-Society-of-Transplant-Physicians Alpert, S., Lewis, N. P., Ross, H., Fowler, M., Valantine, H. A. WILLIAMS & WILKINS. 1995: 1478–85


    The mechanisms underlying contractile dysfunction following heart transplantation are poorly defined. To investigate the role of cytotoxic T cells (CTL) in cardiac transplant rejection, and during episodic contractile dysfunction, we performed a prospective study analyzing the expression of granzyme A and perforin, two functional markers of activated CTL. Sixteen consecutive patients were analyzed during the first year posttransplantation. All patients received induction therapy with OKT-3 and received standard three-drug immunosuppression therapy. Rejection status was monitored using routine surveillance endomyocardial biopsy and graded according to the ISHLT scale. Granzyme A and perforin mRNA were detected by reverse transcription PCR at the time of each routine biopsy. A total of 64/123 biopsies were positive for granzyme expression, while 38/123 samples were positive for perforin expression. LV function was monitored using M-mode derived fractional shortening and Doppler assessment of diastolic function (isovolumic relaxation time [IVRT] and pressure half-time [P1/2]). As expected, the presence of granzyme A message was associated with rejection score (ANOVA, P = 0.001). In addition, granzyme A expression was correlated with a decrease in diastolic function (chi 2 = 6.4, P < 0.02), but was not associated with systolic function. The presence of perforin message was not correlated with functional changes or with rejection grade, but was associated with granzyme expression (chi 2 = 9.11, P = 0.0025). These studies suggest that the presence of granzyme A message may be an important predictor of graft function.

    View details for Web of Science ID A1995TN23000019

    View details for PubMedID 8545878

  • Selecting candidates for cardiac transplantation. How to assess exclusion criteria and predict who will benefit. The Journal of critical illness Rickenbacher, P. R., Haywood, G., Fowler, M. B. 1995; 10 (3): 199-206


    The fundamental indication for cardiac transplantation is advanced heart failure that is unresponsive to medical therapy in patients with coronary artery disease or dilated cardiomyopathy. Other potential indications include advanced valvular or congenital heart disease and, more rarely, hypertrophic or restrictive cardiomyopathy, sarcoidosis, myocarditis, and primary unresectable cardiac tumors. Determining which patients have symptoms that are truly refractory to medical therapy is difficult. Ejection fraction or clinical status during acute decompensation is not a sufficient criterion for candidacy.

    View details for PubMedID 10150403

  • Spontaneous reversibility of catecholamine-induced cardiotoxicity in rats. The American journal of cardiovascular pathology Deisher, T. A., Ginsburg, R., Fowler, M. B., Billingham, M. E., Bristow, M. R. 1995; 5 (1): 79-88


    In order to evaluate the chronic in vivo effects of excessive catecholamine levels, and the potential for spontaneous reversibility of these effects, we employed a chronic two-week infusion of epinephrine in rats. Epinephrine infusion resulted in myocyte hypertrophy, left ventricular fibrotic degenerative changes, diminished response to adrenergic stimuli, and enhanced left ventricular papillary contractile responses to calcium. Two weeks after cessation of the epinephrine infusion, left ventricular fibrotic degenerative changes were reduced, and responses to adrenergic stimuli were partially restored. However, myocyte hypertrophy and the enhanced responses to calcium persisted in these animals. This study indicates the potential for spontaneous reversal of some of epinephrine's toxic effects, and further implies that the loss in adrenergic sensitivity in epinephrine-treated animals may be a desensitization phenomenon, while the alterations in calcium response are less readily reversed.

    View details for PubMedID 8838159

  • INCIDENCE OF MYOCARDITIS IN PERIPARTUM CARDIOMYOPATHY AMERICAN JOURNAL OF CARDIOLOGY Rizeq, M. N., Rickenbacher, P. R., Fowler, M. B., Billingham, M. E. 1994; 74 (5): 474-477


    Peripartum cardiomyopathy (PC), an uncommon cause of peripartum heart failure, is defined as a cardiomyopathy presenting in the last trimester of pregnancy or the first 6 months postpartum, without evidence of preexisting cardiovascular disease. The etiology of PC and idiopathic dilated cardiomyopathy (IDC) remains uncertain. Several reports have addressed possible differences in clinical presentation and prognosis between these groups. A relatively high incidence of myocarditis has been recently reported in patients with PC, raising the possibility that this may represent a distinct difference between this condition and IDC. A retrospective review of endomyocardial biopsy specimens from 34 patients fulfilling the criteria for a diagnosis of PC was therefore performed to further evaluate this finding. Results indicate a lower incidence of myocarditis (8.8%, 3 of 34) than that reported in other studies. This incidence was comparable to that found in an age- and sex-matched control population undergoing transplantation for IDC (9.1%, 2 of 22). Factors that may influence the diverse range in the reported incidence of myocarditis are discussed.

    View details for Web of Science ID A1994PD58800012

    View details for PubMedID 8059728

  • LONG-TERM OUTCOME AFTER HEART-TRANSPLANTATION FOR PERIPARTUM CARDIOMYOPATHY AMERICAN HEART JOURNAL Rickenbacher, P. R., Rizeq, M. N., Hunt, S. A., Billingham, M. E., Fowler, M. B. 1994; 127 (5): 1318-1323


    To elucidate the long-term outcome and frequency of complications after heart transplantation for peripartum cardiomyopathy (PPCM), we compared the courses of eight consecutive patients undergoing transplantation for PPCM with those of nine female age-matched control subjects undergoing transplantation for idiopathic dilated cardiomyopathy (IDCM). No significant differences could be found in baseline variables between the two groups with the exception of the number of pregnancies (2.5 +/- 1.5 vs 0, p = 0.0002). Two patients in each group died during the first 6 months after transplantation, and one in each group died later. Actuarial survival rates were 75% +/- 15% and 78% +/- 14% (p = NS) at 1 year and 60% +/- 18% and 78% +/- 14% (p = NS) at 5 years in PPCM and IDCM patients, respectively. Linearized rejection rates during the first 3 months were 1.85 +/- 0.56 and 1.91 +/- 0.49 (p = NS) and during the second 3 months were 0.18 +/- 0.18 and 0.45 +/- 0.26 (p = NS), respectively. Similarly no significant differences in linearized infection rates were found. Among patients surviving more than 6 months after transplantation, after a mean follow-up period of 4.5 +/- 3.1 years for those with PPCM and 7.8 +/- 3.2 years for those with IDCM, 83% and 100%, respectively, were rehabilitated; hemodynamic findings were normal in all patients and the frequency of other transplant-associated complications was similar in both groups. In conclusion, heart transplantation is a valuable option for patients with PPCM and severe congestive heart failure that is unresponsive to conventional treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1994NJ87900015

    View details for PubMedID 8172060



    Patients with congestive heart failure (CHF) have baseline restrictive and obstructive abnormalities in pulmonary function. Thus, improvement of respiratory parameters may provide a new method for the treatment of CHF. Ipratropium is an inhaled anticholinergic bronchodilator with no reported cardiac or systemic effect. A pilot study was performed to investigate the acute effects of a 72 micrograms inhaled dose of ipratropium bromide on pulmonary function and pulmonary artery pressures in 18 nonsmokers and 11 smokers with severe (New York Heart Association class 2 or 3), stable CHF who were referred for orthotopic cardiac transplantation. An unmatched group of 10 healthy subjects (5 men and 5 women, mean age 36.8 +/- 1.8 years) were studied with pulmonary function testing alone. Forced expiratory volume in 1 second (FEV1) in 15 of 18 nonsmokers with CHF showed a favorable response with a mean improvement of 5.1% (2.74 +/- 0.20 to 2.89 +/- 0.19 liter after drug treatment; p = 0.0026). Forced expiratory flow between 25 and 75% of the forced vital capacity (FEF25-75) improved by 19% (2.50 +/- 0.25 to 3.09 +/- 0.28 liter/s; p = 0.0013). Eight of 11 smokers with CHF responded with a 9.5% increase in FEV1 (2.32 +/- 0.21 to 2.54 +/- 0.19 liter; p = 0.0006) and a 23.2% increase in FEF25-75 (1.82 +/- 0.38 to 2.37 +/- 0.46 liter/s; p = 0.0029). Pulmonary artery pressures, cardiac output, systemic arterial pressures, and cardiac rate and rhythm were unaffected by administration of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1994MT45700010

    View details for PubMedID 8296756

  • BENEFICIAL-EFFECTS OF METOPROLOL IN IDIOPATHIC DILATED CARDIOMYOPATHY LANCET Waagstein, F., Bristow, M. R., Swedberg, K., Camerini, F., Fowler, M. B., Silver, M. A., Gilbert, E. M., Johnson, M. R., GOSS, F. G., Hjalmarson, A. 1993; 342 (8885): 1441-1446


    Several small studies have suggested beneficial effects of long-term beta-blocker treatment in idiopathic dilated cardiomyopathy. Our large multicentre study aimed to find out whether metoprolol improves overall survival and morbidity in this disorder. 383 subjects with heart failure from idiopathic dilated cardiomyopathy (ejection fraction < 0.40) were randomly assigned placebo or metoprolol. 94% were in New York Heart Association functional classes II and III, and 80% were receiving background treatment. A test dose of metoprolol (5 mg twice daily) was given for 2-7 days; those tolerating this dose (96%) entered randomisation. Study medication was increased slowly from 10 mg to 100-150 mg daily. There were 34% (95% CI -6 to 62%, p = 0.058) fewer primary endpoints in the metoprolol than the placebo group; 2 and 19 patients, respectively, deteriorated to the point of needing transplantation and 23 and 19 died. The change in ejection fraction from baseline to 12 months was significantly greater with metoprolol than with placebo (0.13 vs 0.06, p < 0.0001). Pulmonary capillary wedge pressure decreased more from baseline to 12 months with metoprolol than with placebo (5 vs 2 mm Hg, p = 0.06). Exercise time at 12 months was significantly greater (p = 0.046) in metoprolol-treated than in placebo-treated patients. In patients with idiopathic dilated cardiomyopathy, treatment with metoprolol prevented clinical deterioration, improved symptoms and cardiac function, and was well tolerated.

    View details for Web of Science ID A1993ML21700006

    View details for PubMedID 7902479



    We investigated the effects of clentiazem, a 1,5-benzothiazepine calcium antagonist, on epinephrine-induced cardiomyopathy in rats. With 2-week chronic epinephrine infusion, 16 of 30 rats died within 4 days, and severe ischemic lesions and fibrosis of the left ventricles were observed. In epinephrine-treated rats, left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced, but responses to calcium were normal or enhanced compared to controls. Left ventricular alpha and beta adrenoceptor densities were also reduced compared to controls. Treatment with clentiazem prevented epinephrine-induced death (P < .05), and attenuated the ventricular ischemic lesions and fibrosis, in a dose-dependent manner. Left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced compared to controls in groups treated with clentiazem alone, but combined with epinephrine, clentiazem restored left atrial responses and enhanced left ventricular papillary responses to isoproterenol. On the other hand clentiazem did not prevent epinephrine-induced down-regulation of alpha and beta adrenoceptors. Interestingly, clentiazem, infused alone, resulted in decreased adrenergic receptor densities in the left ventricle. Clentiazem also did not prevent the enhanced responses to calcium seen in the epinephrine-treated animals, although the high dose of clentiazem partially attenuated the maximal response to calcium compared to epinephrine-treated animals. In conclusion, clentiazem attenuated epinephrine-induced cardiac injury, possibly through its effect on the adrenergic pathway.

    View details for Web of Science ID A1993LN29300037

    View details for PubMedID 8392553

  • Controlled trials with beta blockers in heart failure: metoprolol as the prototype. American journal of cardiology Fowler, M. B. 1993; 71 (9): 45C-53C


    Early studies of acute beta-blocking drug therapy, such as metoprolol and acebutolol, in patients with idiopathic dilated cardiomyopathy (IDC) and survivors of acute myocardial infarction were interpreted to have detrimental or, at best, neutral effects on cardiac and clinical hemodynamics. Subsequent trials of longer duration with metoprolol versus placebo in patients with IDC demonstrated an "exceptional response" to beta-blocker therapy in some individuals. Hemodynamics and patient demographic characteristics appear not to predict those patients who may or may not benefit. Controlled trials with newer beta-adrenoceptor modulating drugs--such as xamoterol, bucindolol, and carvedilol--have been equivocal in some situations. Xamoterol has been associated with progressive heart failure and increased sudden cardiac deaths, whereas bucindolol improved clinical heart failure symptoms and testing hemodynamic parameters, as did treatment with carvedilol, in patients with ischemic cardiomyopathy. The success of these agents in patients with congestive heart failure may be in their ability to modulate the excessive myocardial stimulation of the beta-adrenergic nervous system while benefitting the dynamics of the peripheral system.

    View details for PubMedID 8096675

  • Beta-blockers in heart failure: potential of carvedilol. Journal of human hypertension Fowler, M. B. 1993; 7: S62-7


    The excessive or inappropriate response of the neuroendocrine system to impaired cardiac performance has become a major therapeutic target in heart failure. While the benefits of ACE inhibition and vasodilation are now established, and the necessary effects of diuretic therapy accepted, there is increasing evidence that in many patients additional benefit would follow modulation of the sympathetic nervous system. Beta-adrenergic blocking drugs improve survival following myocardial infarction and have improved patients with heart failure. Drugs such as carvedilol, which combine vasodilation mediated through alpha-adrenergic blockade with beta-adrenergic blockade have an attractive profile as they unite these two pharmacological actions in a way that may benefit patients with heart failure.

    View details for PubMedID 8098065

  • BETA-ADRENERGIC NEUROEFFECTOR ABNORMALITIES IN THE FAILING HUMAN HEART ARE PRODUCED BY LOCAL RATHER THAN SYSTEMIC MECHANISMS JOURNAL OF CLINICAL INVESTIGATION Bristow, M. R., Minobe, W., Rasmussen, R., Larrabee, P., SKERL, L., Klein, J. W., Anderson, F. L., Murray, J., Mestroni, L., Karwande, S. V., Fowler, M., Ginsburg, R. 1992; 89 (3): 803-815


    In order to investigate the general cause of beta-adrenergic receptor neuroeffector abnormalities in the failing human heart, we measured ventricular myocardial adrenergic receptors, adrenergic neurotransmitters, and beta-adrenergic receptor-effector responses in nonfailing and failing hearts taken from nonfailing organ donors, subjects with endstage biventricular failure due to idiopathic dilated cardiomyopathy (IDC), and subjects with primary pulmonary hypertension (PPH) who exhibited isolated right ventricular failure. Relative to nonfailing PPH left ventricles, failing PPH right ventricles exhibited (a) markedly decreased beta 1-adrenergic receptor density, (b) marked depletion of tissue norepinephrine and neuropeptide Y, (c) decreased adenylate cyclase stimulation in response to the beta agonists isoproterenol and zinterol, and (d) decreased adenylate cyclase stimulation in response to Gpp(NH)p and forskolin. These abnormalities were directionally similar to, but generally more pronounced than, corresponding findings in failing IDC right ventricles, whereas values for these parameters in nonfailing left ventricles of PPH subjects were similar to values in the nonfailing left ventricles of organ donors. Additionally, relative to paired nonfailing PPH left ventricles and nonfailing right ventricles from organ donors, failing right ventricles from PPH subjects exhibited decreased adenylate cyclase stimulation by MnCl2. These data indicate that: (a) Adrenergic neuroeffector abnormalities present in the failing human heart are due to local mechanisms; systemic processes do not produce beta-adrenergic neuroeffector abnormalities. (b) Pressure-overloaded failing right ventricles of PPH subjects exhibit decreased activity of the catalytic subunit of adenylate cyclase, an abnormality not previously described in the failing human heart.

    View details for Web of Science ID A1992HH51300013

    View details for PubMedID 1311717



    Patients with pulmonary hypertension are at risk of developing fatal right heart failure after heart transplantation. To evaluate this risk potential, candidates for heart transplantation are screened by measuring rest right heart pressures and the response to nitroprusside. To test the validity of this approach, the influence of pretransplantation right heart catheterization data on outcome after transplantation was analyzed in 293 of 301 consecutive patients. Patients with a pulmonary vascular resistance greater than 2.5 Wood units measured at baseline study had a 3-month mortality rate of 17.9% compared with 6.9% in patients with resistance less than or equal to 2.5 units (p less than 0.02). Patients with a pulmonary vascular resistance greater than 2.5 units at baseline study could be differentiated further according to their hemodynamic response to nitroprusside; those whose resistance could be reduced to less than or equal to 2.5 units with a stable systemic systolic pressure greater than or equal to 85 mm Hg had a 3-month mortality rate of only 3.8%. In contrast, patients whose pulmonary vascular resistance could not be reduced to less than 2.5 units, and those whose resistance could be reduced to less than or equal to 2.5 units but only at the expense of systemic hypotension (systolic pressure less than or equal to 85 mm Hg) had a 3-month mortality rate of 40.6% and 27.5%, respectively. Furthermore, all 10 patients who died of right heart failure belonged to the latter two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1992GX83600008

    View details for PubMedID 1729345

  • The influence of preoperative patient characteristics on early and late survival following cardiac transplantation. Circulation Costard-Jäckle, A., Hill, I., Schroeder, J. S., Fowler, M. B. 1991; 84 (5): III329-37


    In an attempt to identify the preoperative factors that influence survival following cardiac transplantation, we retrospectively analyzed multiple demographic, clinical, and hemodynamic data of 301 consecutive patients who underwent cardiac transplantation between December 1980 and July 1988 (cyclosporine era). Univariate and multivariate regression analyses revealed that the two most deleterious risk factors for premature death following transplantation were pulmonary hypertension not responsive to vasodilator challenge and preoperative requirement of hemodynamic support (intravenous inotropes or mechanical assistance). The combination of these two independent risk factors was an even stronger predictor of mortality (relative risk, 6:1; p less than 0.0001): the 3-month actuarial survival rate of the 20 patients with this combination was 30.3% versus 78.4% of the 47 patients with only pulmonary hypertension, 87.9% of the 42 patients with only the requirement of hemodynamic support, and 95.3% of the 172 patients with neither of these two risk factors. The difference in postoperative mortality between patients with versus those without these two risk factors is due to a higher rate of fatal infectious complications: six of 20 patients (30%) with both risk factors died from infection within 3 months after transplant compared with three deaths among 172 patients (1.7%) with neither of these risk factors. The majority of fatal infections were pulmonary. There were significantly more fatal and nonfatal infectious episodes in patients with one or both of these risk factors.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for PubMedID 1934427



    The sympathetic nervous system is chronically activated in heart failure. This results in a reduction in numbers and sensitivity of beta-receptors, making the heart less responsive to the actions of catecholamines. This is specific to beta-receptors, the adenycyclase system being largely unaffected. Sympathomimetic agents are still used in patients with heart failure to augment cardiac contractility, but tachyphylaxis limits their long-term usefulness, and they may actually cause further myocardial damage. On the other hand, beta-blockade can improve sensitivity to catecholamines and cardiac action in some patients with severe left ventricular dysfunction, although this treatment can be hazardous and cannot yet be routinely recommended. Partial beta-agonists are theoretically useful since they can provide baseline sympathetic drive while protecting the heart against excessive sympathetic stimulation and down-regulation of beta-receptors. Xamoterol, a partial agonist with half the sympathetic activity of isoprenaline, has been shown to be superior to placebo and to digoxin in patients with mild to moderate heart failure.

    View details for Web of Science ID A1990DF55900003

    View details for PubMedID 1971585

  • Selection of patients for cardiac transplantation. Cardiology clinics Vagelos, R., Fowler, M. B. 1990; 8 (1): 23-38


    In order to appropriately allocate the precious resource of donor organs for cardiac transplantation, one must adequately assess the prognosis of the prospective recipient with or without transplantation. This requires knowledge of the natural history of heart failure as well as those parameters by which it is evaluated. It also requires knowledge of those factors that make patients appropriate versus inappropriate surgical candidates. This article approaches both these necessary areas of patient evaluation.

    View details for PubMedID 2407358

  • HEMODYNAMIC AND RENAL EFFECTS OF ATRIAL-NATRIURETIC-PEPTIDE IN CONGESTIVE HEART-FAILURE AMERICAN JOURNAL OF CARDIOLOGY Fifer, M. A., Molina, C. R., QUIROZ, A. C., Giles, T. D., Herrmann, H. C., DESCHEERDER, I. R., Clement, D. L., Kubo, S., Cody, R. J., Cohn, J. N., Fowler, M. B. 1990; 65 (3): 211-216


    The hemodynamic and renal effects of anaritide (human atrial natriuretic peptide 102-126), a synthetic analog of atrial natriuretic peptide, were evaluated in 35 patients with chronic New York Heart Association class II to IV heart failure. There were 32 men and 3 women, aged 33 to 75 (mean +/- standard error of the mean 56 +/- 2) years. In the first phase of the study, right-sided heart catheterization was performed, and anaritide was administered as 1-hour infusions. The rate of the infusion varied among patients from 0.03 to 0.3 micrograms/kg/min. In response to anaritide, there were decreases in mean systemic arterial (94 +/- 2 to 87 +/- 2 mm Hg), right atrial (10 +/- 1 to 8 +/- 1 mm Hg), mean pulmonary arterial (33 +/- 2 to 28 +/- 2 mm Hg) and pulmonary artery wedge (22 +/- 2 to 15 +/- 2 mm Hg) pressures (all p less than 0.05). Cardiac index increased (2.39 +/- 0.15 to 2.62 +/- 0.15 liters/min/m2, p less than 0.05) and heart rate was unchanged. Systemic vascular resistance decreased significantly, but pulmonary vascular resistance was unchanged. There were increases in urine volume (1.6 +/- 0.2 to 2.3 +/- 0.4 ml/min), sodium excretion (47 +/- 13 to 74 +/- 20 muEq/min) and fractional excretion of sodium (0.41 +/- 0.11 to 0.59 +/- 0.14%, all p less than 0.05), while potassium excretion and creatinine clearance did not change. In the second phase of the study, patients received 2-hour infusions of anaritide (0.03 to 0.6 micrograms/kg/min) and placebo with noninvasive monitoring.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1990CH30600017

    View details for PubMedID 2136969


    View details for Web of Science ID A1989AN58000024

    View details for PubMedID 2773802



    Severe heart failure is associated with a reduction in myocardial beta-adrenergic receptor density and an impaired contractile response to catecholamine stimulation. Metoprolol was administered during a 6-month period to 14 patients with dilated cardiomyopathy to examine its effects on these abnormalities. The mean daily dose of metoprolol for the group was 105 mg (range, 75-150 mg). Myocardial beta-receptor density, resting hemodynamic output, and peak left ventricular dP/dt response to dobutamine infusions were compared in 9, 14, and 7 patients, respectively, before and after 6 months of metoprolol therapy while the patients were on therapy. The second hemodynamic study was performed 1-2 hours after the morning dose of metoprolol had been given. Myocardial beta-receptor density increased from 39 +/- 7 to 80 +/- 12 fmol/mg (p less than 0.05). Resting hemodynamic output showed a rise in stroke work index from 27 +/- 4 to 43 +/- 3 g/m/m2, p less than 0.05, and ejection fraction rose from 0.26 +/- 0.03 to 0.39 +/- 0.03 after 6 months of metoprolol therapy, p less than 0.05. Before metoprolol therapy, dobutamine caused a 21 +/- 4% increase in peak positive left ventricular dP/dt; during metoprolol therapy, the same dobutamine infusion rate increased peak positive dP/dt by 74 +/- 18% (p less than 0.05). Thus, long-term metoprolol therapy is associated with an increase in myocardial beta-receptor density, significant improvement in resting hemodynamic output, and improved contractile response to catecholamine stimulation. These changes indicate a restoration of beta-adrenergic sensitivity associated with metoprolol therapy, possibly related to the observed up-regulation of beta-adrenergic receptors.

    View details for Web of Science ID A1989T597000002

    View details for PubMedID 2537158

  • EFFECT OF PREOPERATIVE HEMODYNAMIC SUPPORT ON SURVIVAL AFTER CARDIAC TRANSPLANTATION CIRCULATION OCONNELL, J. B., Renlund, D. G., Robinson, J. A., Fowler, M. B., Oyer, P. E., Pifarre, R., Grady, K. L., MULLIN, A. V., MENLOVE, R. L., Gay, W. A., Bristow, M. R. 1988; 78 (5): 78-82


    The cardiac release and total body and renal clearances and the hemodynamic, renal and endocrine effects of increasing doses of atrial natriuretic peptide were investigated in 12 patients with severe chronic congestive heart failure. Immunoreactive arterial plasma levels of atrial natriuretic peptide were 10-fold higher than normal and there was no correlation between aortic atrial natriuretic peptide and cardiac filling pressures. The heart released atrial natriuretic peptide into the coronary sinus. The kidney, though a major clearance site, accounted for only 33% of the total body clearance. Administration of 0.3 micrograms/kg per min atrial natriuretic peptide produced significant changes in heart rate (95 +/- 4 to 85 +/- 4 beats/min) and mean arterial (92 +/- 8 to 77 +/- 9 mm Hg), right atrial (13 +/- 3 to 8 +/- 2 mm Hg) and mean pulmonary artery occluded (27 +/- 3 to 14 +/- 3 mm Hg) pressures. Atrial natriuretic peptide increased cardiac index (2.25 +/- 0.18 to 2.83 +/- 0.3 liters/min per m2) and stroke work index (21 +/- 1.5 to 29 +/- 3.4 g/m2), whereas systemic vascular resistance (1,424 +/- 139 to 1,033 +/- 97 decreased. Infusion of 0.1 microgram/kg per min atrial natriuretic peptide increased urinary flow 128%, fractional excretion of sodium 133% and fractional excretion of potassium 35%. The filtration fraction increased from 29 +/- 2 to 31 +/- 4%. This represented a disproportionate rise in glomerular filtration rate over renal plasma flow. Plasma aldosterone and norepinephrine decreased whereas plasma renin activity remained unchanged. In association with these hemodynamic, excretory and endocrine changes, the urinary excretion of cyclic guanosine monophosphate doubled. Placebo had no effect. These results showed that, despite high circulating levels of atrial natriuretic peptide, administration of this hormone in heart failure is associated with potentially beneficial hemodynamic, renal and endocrine effects.

    View details for Web of Science ID A1988P162200024

    View details for PubMedID 2967855

  • ORTHOTOPIC CARDIAC TRANSPLANTATION FOR UNIVENTRICULAR HEART ANNALS OF THORACIC SURGERY Macoviak, J. A., Baldwin, J. C., Ginsburg, R., Fowler, M., Valentine, H., Oyer, P. E., Stinson, E. B. 1988; 45 (1): 85-86


    The technical aspects of orthotopic cardiac transplantation for univentricular heart in a 22-year-old man are discussed. Abnormal pulmonary artery anatomy resulted in right ventricular failure, which was successfully treated.

    View details for Web of Science ID A1988M025100020

    View details for PubMedID 3337582



    Although the success of cardiac transplantation has encouraged earlier referral of potential candidates, those with mild symptoms of heart failure are frequently considered "too well" for transplantation. Outcome was investigated for 28 patients with non-ischemic dilated cardiomyopathy and ejection fraction of 25 percent or less who were denied transplantation due to lack of severe symptoms. One-year survival without transplantation was 46 percent. Low stroke volume and history of ventricular arrhythmias were independent predictors of early mortality. High risk, defined as either stroke volume of 40 ml or less or history of ventricular arrhythmia, identified 13 of 14 patients who did not survive one year and only one of 12 one-year survivors (p less than 0.001). Low stroke volume predicted hemodynamic failure (p less than 0.05) whereas arrhythmic history predicted sudden death (p less than 0.001). Clinical status improved in only six patients, all of whom had symptom duration of seven or less months at initial evaluation (p less than 0.001). Thus, patients referred to transplantation for dilated cardiomyopathy with an ejection fraction of 25 percent or less have a poor prognosis even if symptoms are mild. Patients with high hemodynamic risk may require early transplantation, whereas those with high arrhythmia risk may require other aggressive therapy in order to avoid transplantation until symptoms become severe.

    View details for Web of Science ID A1987K745100010

    View details for PubMedID 3314498

  • HYPOXIC PULMONARY VASOCONSTRICTION PERSISTS IN THE HUMAN TRANSPLANTED LUNG CLINICAL SCIENCE Robin, E. D., Theodore, J., Burke, C. M., Oesterle, S. N., Fowler, M. B., Jamieson, S. W., Baldwin, J. C., Morris, A. J., Hunt, S. A., VANKESSEL, A., Stinson, E. B., Shumway, N. E. 1987; 72 (3): 283-287


    The preservation of hypoxic pulmonary vasoconstriction (HPV) in the denervated lung was studied in five human heart-lung transplant recipients. All five patients showed significant increases in mean pulmonary artery pressure and pulmonary vascular resistance during hypoxic exposure, returning toward normoxic values during recovery. Aside from PAO2 and Pao2, other factors known to influence pulmonary vascular resistance did not change significantly during the hypoxic period. There was no relation between the length of the post-transplantation period and the intensity of HPV, suggesting that reinnervation of the pulmonary vascular bed did not account for persistent HPV and that HPV persists in the human transplanted lung despite the loss of autonomic neural innervation.

    View details for Web of Science ID A1987G007200004

    View details for PubMedID 3545645


    View details for Web of Science ID A1987G101500265

    View details for PubMedID 3547937