Bio

Clinical Focus


  • Amyloidosis
  • Heart Failure
  • Cardiotoxicity of Cancer Therapies
  • Cardiovascular Disease
  • Sarcoidosis

Academic Appointments


Administrative Appointments


  • Program Director, Internal Medicine Residency Training Program (2011 - Present)
  • Co-Director, Stanford Amyloid Center (2008 - Present)
  • Sr. Associate Program Director, Internal Medicine Residency Training Program (2009 - 2011)
  • Associate Director, Coronary Care Unit (CCU) (2008 - 2009)

Honors & Awards


  • David W. Rytand Award for Excellence in Clinical Teaching by a Department of Medicine faculty member, Stanford University Department of Internal Medicine (2009, 2010)
  • First Author - Selected as one of 15 most important heart failure articles in 2007, Journal of the American College of Cardiology (2008)
  • Clinical Research Award, Stanford Univ. Division of Cardiovascular Medicine (2007)
  • Timothy F. Beckett, Jr. Award for Excellence in Teaching by a Medicine Fellow, Stanford Univ. Dept. of Internal Medicine (2006)
  • Clinical Excellence Award, Stanford University Division of Cardiovascular Medicine (2006)
  • National Research Fellowship Award, Heart Failure Society of America (2006)
  • First Author - Selected as one of 10 most important heart failure articles in 2004, Journal of the American College of Cardiology (2005)
  • National Associates' Research Award, American College of Physicians/American Society of Internal Medicine (2004)
  • Charles Dorsey Armstrong Clinical Excellence Award, Stanford University Dept. of Internal Medicine (2003)
  • Outstanding Clinical Teaching Award, Stanford University Dept. of Internal Medicine (2002, 2003)
  • Francis G. Ebaugh, Jr. Research Award, Stanford University Dept. of Internal Medicine (2001, 2002, 2003)
  • M.D. with Honors (highest distinction by U. of Chicago), University of Chicago Pritzker School of Medicine (2000)
  • Calvin Fentress Research Fellowship, University of Chicago Pritzker School of Medicine (1999)

Professional Education


  • Board Certification: Advanced Heart Failure and Transplant Cardiology, American Board of Internal Medicine (2006)
  • Fellowship:Stanford University School of Medicine (2007) CA
  • Residency:Stanford University School of Medicine (2004) CA
  • Residency:Stanford University School of Medicine (2003) CA
  • Board Certification: Cardiovascular Disease, American Board of Internal Medicine (2007)
  • Board Certification: Internal Medicine, American Board of Internal Medicine (2003)
  • Chief Resident, Stanford University, Internal Medicine (2004)
  • Internship:Stanford University School of Medicine (2001) CA
  • M.D. with Honors, University of Chicago, Medicine (2000)
  • B.A., Northwestern University, Biology/Neuroscience (1996)
  • F.A.C.P., American College of Physicians, Internal Medicine (2010)
  • F.A.C.C., American College of Cardiology, Cardiology (2008)
  • Chief Fellow, Stanford University, Cardiovascular Medicine (2007)
  • Medical Education:University of Chicago Pritzker (2000) IL

Research & Scholarship

Current Research and Scholarly Interests


Dr. Witteles' research focuses on three major areas:

1) Cardiac toxicity of cancer therapies -- Studying optimal prevention and treatment strategies for patients who develop heart failure and other cardiac toxicity as a consequence of cancer therapies, as well as studies to better understand the mechanisms/patterns of toxicity for multiple chemotherapeutic agents.

2) Amyloidosis -- As Co-Director of the Stanford Amyloid Center, Dr. Witteles works with a team of investigators to explore novel therapies for amyloidosis and to better understand the mechanisms underlying the disease. This work ranges from clinical trials for multiple types of amyloidosis (AL, ATTR, AA), to defining the role of organ transplantation and pacemakers/defibrillators, to partnering with basic science labs to explore basic principles of pathogenesis.

3) Insulin resistant cardiomyopathy -- Translational research studies to better define the contribution that insulin resistant makes (as a primary contributor) to nonischemic dilated cardiomyopathy, including PET-imaging studies of myocardial glucose uptake.

Studies of physiology/mechanisms include:
1) Relationship of insulin resistance and nonischemic cardiomyopathy. Myocardial glucose metabolism is assessed with PET imaging before/after pharmacologic interventions.

2) Cardiac resynchronization: Exploration of optimal programming methods for timing intervals with biventricular pacing devices using echocardiography and thoracic impedance measurements.

Clinical trials/studies include:

1) Cancer-therapy related cardiotoxicity: Clinical trials to test novel screening and intervention methods to prevent cancer-therapy associated cardiotoxicity from multiple agents (anthracyclines, trastuzumab, tyrosine kinase inhibitors)

2) Cardiorenal syndrome: A large completed double-blind, randomized clinical trial evaluated the role of nesiritide in treating cardiorenal syndrome. Current ongoing trials include studies of a novel natriuretic-peptide (outpatient study) and an adenosine antagonist (inpatient study).

3) Amyloidosis: Clinical trials of novel therapies for amyloidosis

Clinical Trials


  • Verubulin, Radiation Therapy, and Temozolomide to Treat Patients With Newly Diagnosed Glioblastoma Multiforme Not Recruiting

    This, international, multi-center, Phase 2 study of verubulin will be conducted in patients with newly diagnosed Glioblastoma Multiforme (GBM). The study will be conducted in two parts. Part A is an open-label dose finding study that will determine the safety and tolerability of verubulin in combination with standard treatment. Part B is a randomized open-label study that will investigate progression-free survival and overall survival of patients receiving verubulin, at the dose determined in Part A, in combination with standard treatment versus standard treatment alone.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cathy Recht, (650) 725 - 8630.

    View full details

  • Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy Recruiting

    This study will investigate the efficacy, safety, and tolerability of an oral dose of 20 mg or 80 mg tafamidis meglumine soft gel capsules in comparison to placebo and given once daily, in addition to standard of care, for 30 months in subjects diagnosed with transthyretin cardiomyopathy (familial and wild-type). The study is designed to assess the potential for benefit from treatment with tafamidis relative to placebo based on all-cause mortality and frequency of cardiovascular-related hospitalizations.

    View full details

  • 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

  • Defining the Role of Insulin Resistance in 'Idiopathic' Dilated Cardiomyopathy Recruiting

    This study will investigate the effects of rosiglitazone, 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. The primary purpose of the study is to determine whether treatment with an insulin-sensitizing medication will improve the heart's ability to metabolize glucose (sugar).

    View full details

Teaching

2013-14 Courses


Postdoctoral Advisees


Publications

Journal Articles


  • Implantable cardioverter-defibrillator placement in patients with cardiac amyloidosis HEART RHYTHM Varr, B. C., Zarafshar, S., Coakley, T., Liedtke, M., Lafayette, R. A., Arai, S., Schrier, S. L., Witteles, R. M. 2014; 11 (1): 158-162

    View details for DOI 10.1016/j.hrthm.2013.10.026

    View details for Web of Science ID 000329119200027

    View details for PubMedID 24121001

  • Variation in Use of Left Ventriculography in the Veterans Affairs Health Care System CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Heidenreich, P. A., Lin, S., Knowles, J. W., Perez, M., Maddox, T. M., Ho, M. P., Rumsfeld, J. S., Sahay, A., Massie, B. M., Tsai, T. T., Witteles, R. M. 2013; 6 (6): 687-693

    Abstract

    Contrast left ventriculography is a method of measuring left ventricular function usually performed at the discretion of the invasive cardiologist during cardiac catheterization. We sought to determine variation in the use of left ventriculography in the Veterans Affairs (VA) Health Care System.We identified adult patients who underwent cardiac catheterization including coronary angiography between 2000 and 2009 in the VA Health Care System. We determined patient and hospital predictors of the use of left ventriculography as well as the variation in use across VA facilities. Results were validated using data from the VA's Clinical Assessment, Reporting, and Tracking (CART) program. Of 457 170 cardiac catheterization procedures among 336 853 patients, left ventriculography was performed on 263 695 (58%) patients. Use of left ventriculography decreased over time (64% in 2000 to 50% in 2009) and varied markedly across facilities (<1->95% of cardiac catheterizations). Patient factors explained little of the large variation in use between facilities. When the cohort was restricted to those with an echocardiogram in the prior 30 days and no intervening event, left ventriculography was still performed in 50% of cases.There is large variation in the use of left ventriculography across VA facilities that is not explained by patient characteristics.

    View details for DOI 10.1161/CIRCOUTCOMES.113.000199

    View details for Web of Science ID 000330362400017

    View details for PubMedID 24192569

  • Underestimating Cardiac Toxicity in Cancer Trials: Lessons Learned? JOURNAL OF CLINICAL ONCOLOGY Witteles, R. M., Telli, M. 2012; 30 (16): 1916-1918

    View details for DOI 10.1200/JCO.2011.40.4012

    View details for Web of Science ID 000304596800010

    View details for PubMedID 22454419

  • Use and overuse of left ventriculography AMERICAN HEART JOURNAL Witteles, R. M., Knowles, J. W., Perez, M., Morris, W. M., Spettell, C. M., Brennan, T. A., Heidenreich, P. A. 2012; 163 (4): 617-?

    Abstract

    Left ventriculography provided the first imaging of left ventricular function and was historically performed as part of coronary angiography despite a small but significant risk of complications. Because modern noninvasive imaging techniques are more accurate and carry smaller risks, the routine use of left ventriculography is of questionable utility. We sought to analyze the frequency that left ventriculography was performed during coronary angiography in patients with and without a recent alternative assessment of left ventricular function.We performed a retrospective analysis of insurance claims data from the Aetna health care benefits database including all adults who underwent coronary angiography in 2007. The primary outcome was the concomitant use of left ventriculography during coronary angiography.Of 96,235 patients who underwent coronary angiography, left ventriculography was performed in 78,705 (81.8%). Use of left ventriculography was high in all subgroups, with greatest use in younger patients, those with a diagnosis of coronary disease, and those in the Southern United States. In the population who had undergone a very recent ejection fraction assessment by another modality (within 30 days) and who had had no intervening diagnosis of new heart failure, myocardial infarction, hypotension, or shock (37,149 patients), left ventriculography was performed in 32,798 patients (88%)-a rate higher than in the overall cohort.Left ventriculography was performed in most coronary angiography cases and often when an alternative imaging modality had been recently completed. New clinical practice guidelines should be considered to decrease the overuse of this invasive test.

    View details for DOI 10.1016/j.ahj.2011.12.018

    View details for Web of Science ID 000303106800023

    View details for PubMedID 22520528

  • Heart transplantation and cardiac amyloidosis: Approach to screening and novel management strategies JOURNAL OF HEART AND LUNG TRANSPLANTATION Varr, B. C., Liedtke, M., Arai, S., Lafayette, R. A., Schrier, S. L., Witteles, R. M. 2012; 31 (3): 325-331

    Abstract

    Limited data exist regarding screening methods and outcomes for orthotopic heart transplantation (OHT) in cardiac amyloidosis. As a result, uncertainty exists over the best approach to OHT for cardiac amyloidosis and for the timing of critical post-transplant therapies. This article reviews 6 patients who underwent OHT for cardiac amyloidosis at the Stanford University Amyloid Center from 2008 to present. All patients with light-chain amyloidosis received chemotherapy in the interval between OHT and autologous hematopoietic stem cell transplant. Five patients remain alive up to 25 months after OHT, without evidence of recurrent cardiac amyloid deposition. A novel strategy of OHT, followed by light-chain suppressive chemotherapy before autologous hematopoietic stem cell transplant, is feasible for patients with light-chain amyloidosis.

    View details for DOI 10.1016/j.healun.2011.09.010

    View details for Web of Science ID 000300806500015

    View details for PubMedID 22051505

  • 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-?

    Abstract

    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 Web of Science ID 000307494700006

    View details for PubMedID 21749885

  • Radiation Therapy for Breast Cancer Buyer Beware JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Witteles, R. M. 2011; 57 (4): 453-454

    View details for DOI 10.1016/j.jacc.2010.08.637

    View details for Web of Science ID 000286376500011

    View details for PubMedID 21251586

  • Left Ventricular Dysfunction in Patients Receiving Cardiotoxic Cancer Therapies Are Clinicians Responding Optimally? JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Yoon, G. J., Telli, M. L., Kao, D. P., Matsuda, K. Y., Carlson, R. W., Witteles, R. M. 2010; 56 (20): 1644-1650

    Abstract

    The purpose of this study was to examine treatment practices for cancer therapy-associated decreased left ventricular ejection fraction (LVEF) detected on echocardiography and whether management was consistent with American College of Cardiology/American Heart Association guidelines.Patients treated with anthracyclines or trastuzumab are at risk of cardiotoxicity. Decreased LVEF represents a Class I indication for drug intervention according to American College of Cardiology/American Heart Association guidelines.Patients receiving anthracycline or trastuzumab at Stanford University from October 2005 to October 2007 and who had undergone echocardiography before and after receiving an anthracycline or trastuzumab were identified. Chart review examined chemotherapy regimens, cardiac risk factors, imaging results, concomitant medications, and cardiology consultations.Eighty-eight patients received therapy with an anthracycline or trastuzumab and had a pre-treatment and follow-up echocardiogram. Ninety-two percent were treated with anthracyclines, 17% with trastuzumab after an anthracycline, and 8% with trastuzumab without previous treatment with anthracycline. Mean baseline LVEF was 60%, with 14% having a baseline <55%. Forty percent had decreased LVEF (<55%) after anthracycline and/or trastuzumab treatment. Of these patients, 40% received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, 51% beta-blocker therapy, and 54% cardiology consultation. Of patients with asymptomatic decreased LVEF, 31% received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, 35% beta-blocker therapy, and 42% cardiology consultation. Of those with symptomatic decreased LVEF, 67% received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, 100% beta-blocker therapy, and 89% cardiology consultation.Many cancer survivors are not receiving treatment consistent with heart failure guidelines. There is substantial opportunity for collaboration between oncologists and cardiologists to improve the care of oncology patients receiving cardiotoxic therapy.

    View details for DOI 10.1016/j.jacc.2010.07.023

    View details for Web of Science ID 000283737600007

    View details for PubMedID 21050974

  • Heart Failure in Hispanics JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Vivo, R. P., Krim, S. R., Cevik, C., Witteles, R. M. 2009; 53 (14): 1167-1175

    Abstract

    Although large-scale heart failure (HF) studies in Hispanic Americans are lacking, some compelling data indicate that they are a particularly vulnerable population and underscore the need for further research. Hispanics comprise the largest and fastest-growing ethnic group in the U.S., in whom the impact of this burgeoning public health problem may be magnified. Current data show that Hispanics with HF are more likely to be younger and underinsured than non-Hispanic whites. They have higher rates of readmissions but have lower in-hospital and short-term mortality rates. Epidemiologic studies demonstrate that Hispanics have excessive rates of diabetes, obesity, dyslipidemia, and metabolic syndrome. Although hypertension and ischemic heart disease are established risk factors in this ethnic group, it may be considered that insulin resistance plays a significant role in the pathogenesis of HF in Hispanics, accounting for their inordinate cardiometabolic risk burden and the growing evidence of novel metabolic risk factors for HF. Hispanics encounter multiple barriers to health care influenced by socioeconomic, linguistic, and cultural factors that, in turn, have an adverse impact on disease prognosis. Recognition of predominant risk factors and health care disparities in this population is crucial to tailoring appropriate management strategies. This review summarizes epidemiologic and clinical data on Hispanics with HF, details risk factors and health care impediments, and presents an agenda for future investigation.

    View details for DOI 10.1016/j.jacc.2008.12.037

    View details for Web of Science ID 000264724500001

    View details for PubMedID 19341856

  • Clinical problem-solving. Fool's Gold. New England journal of medicine Leeper, N. J., Dhaliwal, G., Saint, S., Witteles, R. M. 2008; 359 (19): 2035-2041

    View details for DOI 10.1056/NEJMcps0802668

    View details for PubMedID 18987372

  • Insulin-resistant cardiomyopathy JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Witteles, R. M., Fowler, M. B. 2008; 51 (2): 93-102

    Abstract

    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 Web of Science ID 000252422800001

    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

    Abstract

    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; http://www.clinicaltrials.gov/ct/show/NCT00186329?order=1; NCT00186329).

    View details for DOI 10.1016/j.jacc.2007.03.071

    View details for Web of Science ID 000250788300003

    View details for PubMedID 17980248

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

    View details for PubMedID 17386873

  • 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

    Abstract

    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 Web of Science ID 000222421500016

    View details for PubMedID 15234411

  • Lenalidomide, melphalan and dexamethasone in a population of patients with immunoglobulin light chain amyloidosis with high rates of advanced cardiac involvement. Haematologica Dinner, S., Witteles, W., Afghahi, A., Witteles, R., Arai, S., Lafayette, R., Schrier, S. L., Liedtke, M. 2013; 98 (10): 1593-1599

    Abstract

    Immunoglobulin light chain amyloidosis remains incurable despite recent therapeutic advances, and is particularly difficult to treat in patients with amyloid cardiomyopathy. Based on evidence of activity in multiple myeloma, we designed a pilot study of an oral regimen of lenalidomide in combination with dexamethasone and low dose melphalan in order to evaluate its safety and efficacy in patients with amyloidosis, including those with advanced cardiac involvement. Twenty-five patients were enrolled. Ninety-two percent of patients had cardiac involvement by amyloidosis, and 36% of patients met criteria for Mayo Clinic cardiac stage III disease. Patients received up to 9 cycles of treatment, consisting of lenalidomide 10 mg/day orally on days 1 - 21 (28 day cycle); melphalan 0.18mg/kg orally on days 1-4; and dexamethasone 40 mg orally on days 1, 8, 15, 22. High rates (33%) of cardiac arrhythmias and low rates of treatment completion (12.5%) were observed. Ten patients died during the study, all within the first several months of treatment due to acute cardiac events. The overall hematologic response rate was 58%, however organ responses were seen in only 8% of patients. Overall survival at one year was 58%. While we confirmed the hematologic response rates observed with similar regimens, front line treatment with melphalan, lenalidomide and dexamethasone was toxic, ineffective, and did not alter survival outcomes for patients with high risk cardiac disease. Our data highlight the importance of developing novel treatment approaches for amyloid cardiomyopathy. The trial was registered at www.clinicaltrials.gov (NCT00890552).

    View details for DOI 10.3324/haematol.2013.084574

    View details for PubMedID 23716538

  • AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Penchala, S. C., Connelly, S., Wang, Y., Park, M. S., Zhao, L., Baranczak, A., Rappley, I., Vogel, H., Liedtke, M., Witteles, R. M., Powers, E. T., Reixach, N., Chan, W. K., Wilson, I. A., Kelly, J. W., Graef, I. A., Alhamadsheh, M. M. 2013; 110 (24): 9992-9997

    Abstract

    The misassembly of soluble proteins into toxic aggregates, including amyloid fibrils, underlies a large number of human degenerative diseases. Cardiac amyloidoses, which are most commonly caused by aggregation of Ig light chains or transthyretin (TTR) in the cardiac interstitium and conducting system, represent an important and often underdiagnosed cause of heart failure. Two types of TTR-associated amyloid cardiomyopathies are clinically important. The Val122Ile (V122I) mutation, which alters the kinetic stability of TTR and affects 3% to 4% of African American subjects, can lead to development of familial amyloid cardiomyopathy. In addition, aggregation of WT TTR in individuals older than age 65 y causes senile systemic amyloidosis. TTR-mediated amyloid cardiomyopathies are chronic and progressive conditions that lead to arrhythmias, biventricular heart failure, and death. As no Food and Drug Administration-approved drugs are currently available for treatment of these diseases, the development of therapeutic agents that prevent TTR-mediated cardiotoxicity is desired. Here, we report the development of AG10, a potent and selective kinetic stabilizer of TTR. AG10 prevents dissociation of V122I-TTR in serum samples obtained from patients with familial amyloid cardiomyopathy. In contrast to other TTR stabilizers currently in clinical trials, AG10 stabilizes V122I- and WT-TTR equally well and also exceeds their efficacy to stabilize WT and mutant TTR in whole serum. Crystallographic studies of AG10 bound to V122I-TTR give valuable insights into how AG10 achieves such effective kinetic stabilization of TTR, which will also aid in designing better TTR stabilizers. The oral bioavailability of AG10, combined with additional desirable drug-like features, makes it a very promising candidate to treat TTR amyloid cardiomyopathy.

    View details for DOI 10.1073/pnas.1300761110

    View details for Web of Science ID 000320930100085

    View details for PubMedID 23716704

  • The prognostic value of diagnosing concurrent multiple myeloma in immunoglobulin light chain amyloidosis BRITISH JOURNAL OF HAEMATOLOGY Dinner, S., Witteles, W., Witteles, R., Lam, A., Arai, S., Lafayette, R., George, T. I., Schrier, S. L., Liedtke, M. 2013; 161 (3): 367-372

    Abstract

    The prevalence and prognostic value of a concomitant diagnosis of symptomatic or asymptomatic multiple myeloma (MM), as defined by the current International Myeloma Working Group (IMWG) criteria, in patients with immunoglobulin light chain amyloidosis (AL), are unknown. We studied 46 consecutive patients with AL who underwent quantification of serum M-protein and clonal bone marrow plasma cells, as well as a comprehensive evaluation for end organ damage by MM. Using standard morphology and CD138 immunohistochemical staining, 57% and 80% of patients were found to have concomitant MM, respectively. Nine patients exhibited end organ damage consistent with a diagnosis of symptomatic MM. While overall survival was similar between AL patients with or without concurrent myeloma (1-year overall survival 68% vs. 87%; P = 0.27), a diagnosis of symptomatic myeloma was associated with inferior outcome (1-year overall survival 39% vs. 81%; P = 0.005). Quantification of bone marrow plasma cells by both standard morphology and CD138 immunohistochemistry identified a much higher prevalence of concurrent MM in patients with AL than previously reported. Evaluation of bone marrow plasma cell infiltration and presence of myeloma associated end organ damage could be clinically useful for prognostication of patients with AL.

    View details for DOI 10.1111/bjh.12269

    View details for Web of Science ID 000317602300009

    View details for PubMedID 23432783

  • Cardiac Testing to Manage Cardiovascular Risk in Cancer Patients SEMINARS IN ONCOLOGY Davis, M., Witteles, R. M. 2013; 40 (2): 147-155

    Abstract

    Cardiovascular toxicity is one of the most feared complications of cancer treatment. Recent advances in oncologic therapies have resulted in improved cancer outcomes but also a new set of cardiovascular adverse effects. Common toxicities include left ventricular dysfunction/heart failure, hypertension, and myocardial ischemia. Accurate risk stratification allows avoidance of potentially harmful treatments in those patients at greatest risk while maintaining the ability to deliver high doses of effective therapies to the lower-risk population. Cardiac investigations, including echocardiography, nuclear imaging, magnetic resonance imaging, biomarker measurement, blood pressure monitoring, electrocardiography, stress testing, and invasive angiography, can help to risk-stratify selected patients. In this review, common complications are discussed in terms of the factors used to identify patients with elevated risk, the monitoring strategies available, and selected interventions that have been used to modify outcomes in patients identified as being at high risk for cardiac complications of cancer treatment.

    View details for DOI 10.1053/j.seminoncol.2013.01.003

    View details for Web of Science ID 000317870900003

    View details for PubMedID 23540740

  • The Frequency and Severity of Cardiovascular Toxicity From Targeted Therapy in Advanced Renal Cell Carcinoma Patients. JACC. Heart failure Hall, P. S., Harshman, L. C., Srinivas, S., Witteles, R. M. 2013; 1 (1): 72-78

    Abstract

    The purpose of this study was to document the incidence and extent of cardiovascular toxicity among advanced renal cell carcinoma patients treated with newer targeted cancer agents.The potential for targeted cancer agents to induce cardiovascular toxicity has been increasingly recognized, but the overall incidence and extent of toxicity have not been well characterized. Early detection of asymptomatic patients could preempt symptomatic toxicity and reduce treatment-related morbidity and mortality.The incidence of hypertension, left ventricular dysfunction, and heart failure was assessed for all advanced renal cell carcinoma patients treated with targeted therapies at our institution between 2004 and 2011. Grading was performed according to the Common Terminology Criteria for Adverse Events version 4.0.Cardiovascular toxicity developed in 116 of 159 patients (73%), including 52 of 159 patients (33%) when hypertension was excluded. Toxicity varied from occurrences of asymptomatic drops in left ventricular ejection fraction to rises in N-terminal-pro-B-type natriuretic peptide to severe heart failure. The tyrosine kinase inhibitor sunitinib was the agent most frequently used, with 66 of 101 sunitinib-treated patients (65%) developing a form of cardiovascular toxicity, including 32 of 101 patients (32%), excluding hypertension. Other VEGF inhibitors such as bevacizumab, sorafenib, and pazopanib also elicited significant cardiovascular toxicity with incidences ranging from 51% to 68%.The frequency and severity of cardiovascular toxicity in advanced renal cell carcinoma patients treated with targeted cancer therapies are high.

    View details for DOI 10.1016/j.jchf.2012.09.001

    View details for PubMedID 24621801

  • Broken Heart Syndrome (Takotsubo Cardiomyopathy) Triggered by Acute Mania: A Review and Case Report PSYCHOSOMATICS Maldonado, J. R., Pajouhi, P., Witteles, R. 2013; 54 (1): 74-79

    View details for Web of Science ID 000313609900010

    View details for PubMedID 22795622

  • Capecitabine-Induced Chest Pain Relieved by Diltiazem AMERICAN JOURNAL OF CARDIOLOGY Ambrosy, A. P., Kunz, P. L., Fisher, G. A., Witteles, R. M. 2012; 110 (11): 1623-1626

    Abstract

    Five patients with primary colorectal adenocarcinoma or anal squamous cell carcinoma were started on a 2-weeks-on, 1-week-off capecitabine dosing regimen in addition to other chemotherapeutic agents and/or radiation. Within the first few doses, patients experienced chest pain and/or dyspnea at rest or with exertion. Acute electrocardiographic findings suggestive of ischemia were found in some cases at initial presentation, and 1 patient had troponin elevation consistent with an acute ST-segment elevation myocardial infarction. Subsequent ischemia evaluations were not suggestive of clinically significant coronary artery disease. All patients experienced immediate and sustained relief from chest pain after discontinuation of capecitabine and were able to successfully tolerate retreatment using a novel management strategy based on secondary prophylaxis with diltiazem. In conclusion, guidelines for the evaluation of and therapy for capecitabine-induced chest pain are proposed.

    View details for DOI 10.1016/j.amjcard.2012.07.026

    View details for Web of Science ID 000311868000011

    View details for PubMedID 22939579

  • 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

    Abstract

    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 Web of Science ID 000310179900009

    View details for PubMedID 23040117

  • More Than a Frog in the Throat A Case Series and Review of Localized Laryngeal Amyloidosis ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Stevenson, R., Witteles, R., Damrose, E., Arai, S., Lafayette, R. A., Schrier, S., Afghahi, A., Liedtke, M. 2012; 138 (5): 509-511

    View details for Web of Science ID 000305415100012

    View details for PubMedID 22652951

  • Trastuzumab-Related Cardiac Dysfunction JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Telli, M. L., Witteles, R. M. 2011; 9 (2): 243-249

    Abstract

    The use of trastuzumab in the adjuvant and metastatic treatment of breast cancer is associated with both symptomatic and asymptomatic cardiotoxicity. The long-term significance of these events, isolating known cardiotoxic effects of anthracyclines from those of trastuzumab, and the appropriateness of referring to trastuzumab-related cardiotoxicity as reversible rather than responsive to trastuzumab withdrawal and heart failure medical therapy, are issues that continue to be debated. This article provides an overview of the available cardiac safety data from the major trastuzumab clinical trials in breast cancer, highlighting areas of ongoing controversy. Important recent data documenting the occurrence and prognostic use of cardiac troponin I elevations among patients treated with trastuzumab are placed into context with the mechanistic insight these data provide and the implications for clinical practice today.

    View details for Web of Science ID 000287942900005

    View details for PubMedID 21310845

  • Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial LANCET Esler, M. D., Krum, H., Sobotka, P. A., Schlaich, M. P., Schmieder, R. E., Boehm, M., Mahfoud, F., Sievert, H., Wunderlich, N., Rump, L. C., Vonend, O., Uder, M., Lobo, M., Caulfield, M., Erglis, A., Azizi, M., Sapoval, M., Thambar, S., Persu, A., Renkin, J., Schunkert, H., Weil, J., Hoppe, U. C., Walton, T., Scheinert, D., Binder, T., Januszewicz, A., Witkowski, A., Ruilope, L. M., Whitbourn, R., Bruck, H., Downes, M., Luescher, T. F., Jardine, A. G., Webster, M. W., Zeller, T., Sadowski, J., Bartus, K., Straley, C. A., Barman, N. C., Lee, D. P., Witteles, R. M., Bhalla, V., Massaro, J. M. 2010; 376 (9756): 1903-1909

    Abstract

    Activation of renal sympathetic nerves is key to pathogenesis of essential hypertension. We aimed to assess effectiveness and safety of catheter-based renal denervation for reduction of blood pressure in patients with treatment-resistant hypertension.In this multicentre, prospective, randomised trial, patients who had a baseline systolic blood pressure of 160 mm Hg or more (≥150 mm Hg for patients with type 2 diabetes), despite taking three or more antihypertensive drugs, were randomly allocated in a one-to-one ratio to undergo renal denervation with previous treatment or to maintain previous treatment alone (control group) at 24 participating centres. Randomisation was done with sealed envelopes. Data analysers were not masked to treatment assignment. The primary effectiveness endpoint was change in seated office-based measurement of systolic blood pressure at 6 months. Primary analysis included all patients remaining in follow-up at 6 months. This trial is registered with ClinicalTrials.gov, number NCT00888433.106 (56%) of 190 patients screened for eligibility were randomly allocated to renal denervation (n=52) or control (n=54) groups between June 9, 2009, and Jan 15, 2010. 49 (94%) of 52 patients who underwent renal denervation and 51 (94%) of 54 controls were assessed for the primary endpoint at 6 months. Office-based blood pressure measurements in the renal denervation group reduced by 32/12 mm Hg (SD 23/11, baseline of 178/96 mm Hg, p<0·0001), whereas they did not differ from baseline in the control group (change of 1/0 mm Hg [21/10], baseline of 178/97 mm Hg, p=0·77 systolic and p=0·83 diastolic). Between-group differences in blood pressure at 6 months were 33/11 mm Hg (p<0·0001). At 6 months, 41 (84%) of 49 patients who underwent renal denervation had a reduction in systolic blood pressure of 10 mm Hg or more, compared with 18 (35%) of 51 controls (p<0·0001). We noted no serious procedure-related or device-related complications and occurrence of adverse events did not differ between groups; one patient who had renal denervation had possible progression of an underlying atherosclerotic lesion, but required no treatment.Catheter-based renal denervation can safely be used to substantially reduce blood pressure in treatment-resistant hypertensive patients.Ardian.

    View details for DOI 10.1016/S0140-6736(10)62039-9

    View details for Web of Science ID 000285439800031

    View details for PubMedID 21093036

  • 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

    Abstract

    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 Web of Science ID 000277825800009

    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

  • Nesiritide, Heart Failure, and Renal Dysfunction: Irrational Exuberance or Throwing the Baby out with the Bathwater Editorial to: "Impact of Nesiritide on Renal Function and Mortality in Patients Suffering from Heart Failure" by Dontas et al. CARDIOVASCULAR DRUGS AND THERAPY Witteles, R. M. 2009; 23 (3): 183-186

    View details for DOI 10.1007/s10557-009-6169-4

    View details for Web of Science ID 000268200100001

    View details for PubMedID 19353257

  • Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate ANNALS OF ONCOLOGY Telli, M. L., Witteles, R. M., Fisher, G. A., Srinivas, S. 2008; 19 (9): 1613-1618

    Abstract

    In the pivotal phase III metastatic renal cell carcinoma trial, updated data indicates that 21% of sunitinib-treated patients experienced a decline in left ventricular ejection fraction to below normal. This cardiotoxicity was reported to be reversible and without clinical sequelae. We conducted a retrospective analysis of our institutional experience of cardiotoxicity with sunitinib after observing a high incidence of symptomatic heart failure.Patients receiving sunitinib at Stanford University from 1 July 2004 to 1 July 2007 were identified. Medical records were reviewed and those patients experiencing symptomatic grade 3/4 left ventricular systolic dysfunction were identified. Potential cardiac risk factors were analyzed.Forty-eight patients treated with sunitinib were assessable. Seven patients experienced symptomatic grade 3/4 left ventricular dysfunction 22-435 days after initiation of sunitinib. Three patients had persistent cardiac dysfunction after discontinuation of sunitinib and initiation of heart failure therapy. A history of congestive heart failure, coronary artery disease and lower body mass index were factors associated with increased risk.Among patients treated with sunitinib at our institution, 15% developed symptomatic grade 3/4 heart failure. Future studies of sunitinib-related cardiotoxicity are urgently needed, particularly as the oncologic indications for this drug continue to expand.

    View details for DOI 10.1093/annonc/mdn168

    View details for Web of Science ID 000259505400015

    View details for PubMedID 18436521

  • Trastuzumab cardiotoxicity: Clinical management of asymptomatic declines in left ventricular function The American Journal of Hematology/Oncology Telli ML, Witteles RM, Hunt SA, Carlson RW, Guardino AE 2008; 7 (1): 38-41
  • Reversible high-output cardiac failure, an unusual marker of disease status in multiple myeloma Leukemia and Lymphoma Kohrt H, Logan A, Temmins C, Witteles R, Liedtke M, Medeiros B 2008; 49: 581-585
  • Reversibility of trastuzumab cardiotoxicity: Is the concept alive and well? Journal of Clinical Oncology Telli ML, Carlson RW, Guardino AE, Hunt SA, Witteles RM. 2007; 25 (34): 5533-5534
  • Premature ventricular contractions causing pacemaker-mediated tachycardia: A failure of postventricular atrial refractory period after premature ventricular contraction extension? HEART RHYTHM Witteles, R., Engel, G., Wang, P. J., Al-Ahmad, A. 2005; 2 (12): 1389-1390

    View details for DOI 10.1016/j.hrthm.2005.08.023

    View details for Web of Science ID 000234241200023

    View details for PubMedID 16360099

  • B-type natriuretic peptide is effective therapy before cardiac transplantation Annals of Internal Medicine Witteles R, Matsuda K, Fowler MB 2004; 141 (11): 895
  • Parathyroid carcinoma Surgery of the thyroid and parathyroid glands Witteles RM, Straus FH, Koka MLR, Kaplan EL 2002: 46.1-46.13
  • Neuroendocrine tumors of the pancreas The Practice of General Surgery Buell J, Witteles RM, Koka MLR, Sugg SL, Kaplan EL 2002: 1083-1093
  • Adult-onset nesidioblastosis causing hypoglycemia: An important clinical entity and continuing treatment dilemma Archives of Surgery Witteles RM, Straus II FH, Sugg SL, Koka MR, Costa EA, Kaplan EL 2001; 136 (6): 656-663
  • Episodic hypertension associated with sitting on hard surfaces Journal of General Internal Medicine Witteles RM 2001; 16: 70
  • A new provocative test for the diagnosis of pheochromocytoma? American Journal of Anesthesiology Witteles R, Roizen MF 2001; 28: 446-447
  • Sensitivity of diagnostic and localization tests for pheochromocytoma in clinical practice Archives of Internal Medicine Witteles RM, Kaplan EL, Roizen MF 2000; 160 (16): 2521-2524
  • Safe and cost-effective preoperative preparation of patients with pheochromocytoma Anesthesia and Analgesia Witteles RM, Kaplan EL, Roizen MF 2000; 91 (2): 302-304

Conference Proceedings


  • OVERUSE OF LEFT VENTRICULOGRAPHY Witteles, R., Knowles, J. W., Perez, M., Morris, W. H., Spettell, C. M., Brennan, T. A., Heidenreich, P. A. ELSEVIER SCIENCE INC. 2011: E1289-E1289

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