Bio

Bio


Dr. Ronald Witteles is a Cardiologist who specializes in the treatment of patients with Heart Failure. He has particular expertise in the treatment of Amyloidosis, Sarcoidosis, and cardiac complications of cancer therapy (sometimes called "CardioOncology"). He serves as Co-Director of the Stanford Amyloid Center, one of the world's leading centers for the care of patients with amyloidosis, and serves as Co-Director of the Stanford Multidisciplinary Sarcoidosis Program. He is an Associate Editor for JACC: CardioOncology, the world's leading journal dedicated to the field of CardioOncology. Dr. Witteles has published extensively in his areas of expertise, and has won many awards for his excellence in both patient care and education.

Dr. Witteles serves as Program Director for the Stanford Internal Medicine residency program -- directly supervising the training of more than 140 physicians each year. He holds board certification in Internal Medicine, Cardiovascular Disease, and Advanced Heart Failure/Transplant Cardiology.

Clinical Focus


  • Amyloidosis
  • CardioOncology (cardiac complications of cancer therapy)
  • Sarcoidosis
  • Heart Failure
  • Cardiovascular Disease

Academic Appointments


Administrative Appointments


  • Program Director, Internal Medicine Residency Training Program (2011 - Present)
  • Co-Director, Stanford Amyloid Center (2008 - Present)
  • Co-Director, Stanford Multidisciplinary Sarcoidosis Program (2019 - Present)
  • Sr. Associate Program Director, Internal Medicine Residency Training Program (2009 - 2011)
  • Associate Director, Coronary Care Unit (CCU) (2008 - 2009)

Honors & Awards


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

Professional Education


  • Board Certification: Advanced Heart Failure and Transplant Cardiology, American Board of Internal Medicine (2012)
  • 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) 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), to defining the role of organ transplantation and pacemakers/defibrillators, to partnering with basic science labs to explore basic principles of pathogenesis.

2) CardioOncology (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. Dr. Witteles serves as Associate Editor for JACC: CardioOncology, the world's leading journal devoted to the field.

3) Sarcoidosis -- As Co-Director of the Stanford Multidisciplinary Sarcoidosis Program, Dr. Witteles studies novel diagnostic modalities to improve the accuracy of disease diagnosis and the ability to follow responses to treatment of the disease, partners with laboratories to understand the pathogenesis of the disease, and studies new treatments for the disease.

Clinical Trials


  • Open-Label Study of AG10 in Patients With Cardiomyopathy Recruiting

    This prospective, multicenter open-label study will evaluate the long-term safety, tolerability, PK and PD of AG10 administered on a background of stable heart failure therapy.

    View full details

  • Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy Not Recruiting

    This Phase 3 study will investigate the efficacy, safety and tolerability of an oral daily dose of 20 mg or 80 mg tafamidis meglumine capsules compared to placebo in subjects with either transthyretin genetic variants or wild-type transthyretin resulting in amyloid cardiomyopathy.

    Stanford is currently not accepting patients for this trial. For more information, please contact Ed Finn, 650-724-6167.

    View full details

  • Study of Daratumumab for Decreasing Circulating Antibodies in Sensitized Patients Awaiting Solid Organ Transplantation Not Recruiting

    The purpose of this study is to test whether daratumumab, a drug that eliminates antibody-producing plasma cells, can effectively lower the level of preformed antibodies in patients awaiting solid organ transplantation. These preformed antibodies limit the number of donor organs that are compatible for the patients. If daratumumab can effectively remove preformed, donor-specific antibodies, then highly allosensitized patients will have more compatible organs available to them, potentially decreasing transplant waitlist time and reducing mortality.

    Stanford is currently not accepting patients for this trial.

    View full details

Teaching

2019-20 Courses


Publications

All Publications


  • Screening for Transthyretin Amyloid Cardiomyopathy in Everyday Practice. JACC. Heart failure Witteles, R. M., Bokhari, S., Damy, T., Elliott, P. M., Falk, R. H., Fine, N. M., Gospodinova, M., Obici, L., Rapezzi, C., Garcia-Pavia, P. 2019

    Abstract

    Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening, progressive, infiltrative disease caused by the deposition of transthyretin amyloid fibrils in the heart, and can often be overlooked as a common cause of heart failure. Delayed diagnosis due to lack of disease awareness and misdiagnosis results in a poorer prognosis. Early accurate diagnosis is therefore key to improving patient outcomes, particularly in the context of both the recent approval of tafamidis in some countries (including the United States) for the treatment of ATTR-CM, and of other promising therapies under development. With the availability of scintigraphy as an inexpensive, noninvasive diagnostic tool, the rationale to screen for ATTR-CM in high-risk populations of patients is increasingly warranted. Here we propose a framework of clinical scenarios in which screening for ATTR-CM is recommended, as well as diagnostic "red flags" that can assist in its diagnosis among the wider population of patients with heart failure.

    View details for DOI 10.1016/j.jchf.2019.04.010

    View details for PubMedID 31302046

  • Serial Cardiac FDG-PET for the Diagnosis and Therapeutic Guidance of Patients With Cardiac Sarcoidosis JOURNAL OF CARDIAC FAILURE Ning, N., Guo, H., Iagaru, A., Mittra, E., Fowler, M., Witteles, R. 2019; 25 (4): 307–11
  • A Changing Landscape of Mortality for Systemic Light Chain Amyloidosis. JACC. Heart failure Barrett, C. D., Dobos, K., Liedtke, M., Tuzovic, M., Haddad, F., Kobayashi, Y., Lafayette, R., Fowler, M. B., Arai, S., Schrier, S., Witteles, R. M. 2019

    Abstract

    The purpose of this study was to address the overall trends in mortality since the adoption of modern therapies for treatment of systemic amyloidosis, and to reconsider the prognostic significance of individual components of the current staging system.Systemic light chain (AL) amyloidosis involves deposition of immunoglobulin light chains in organs throughout the body and is known to have the highest mortality when significant cardiac involvement is present. Survival has historically been poor but may be improving as systemic therapies continue to advance. This study assesses whether recent advancements in light chain directed therapy have led to improved survival in patients with systemic AL amyloidosis.We reviewed all cases of patients who were evaluated for a new diagnosis of AL amyloidosis at the Stanford Amyloid Center between 2009 and 2016. Patients' stage at diagnosis was determined according to the most commonly used staging system. Clinical data, overall survival from diagnosis, and the independent influence of each component of the staging system were analyzed.At total of 194 patients were identified with a new diagnosis of systemic AL amyloidosis. Median overall survival was 59 months and 6 months for stage 3 and 4 patients, respectively. Median overall survival was not reached in stage 1 and 2 groups, as survival was >50% by the end of the study. Mean overall survival was 118 months, 76 months, 64 months, and 27 months in Stages 1, 2, 3, and 4 patients, respectively. Although N-terminal pro-B-type natriuretic peptide and troponin I concentrations had large effects on prognosis, differences in serum free light chains (dFLC) on initial staging laboratory results ≥18 mg/dl, part of the current staging system, did not contribute significantly to prognosis for values ≥5 mg/dl.Survival for patients with systemic AL amyloidosis has improved for patients at all stages of disease in the present era of rapid advancements in light chain-reducing therapies. Cardiac biomarkers at diagnosis, but not baseline dFLC ≥18 mg/dl, continue to provide important prognostic information.

    View details for DOI 10.1016/j.jchf.2019.07.007

    View details for PubMedID 31606365

  • Expert Consensus Recommendations for the Suspicion and Diagnosis of Transthyretin Cardiac Amyloidosis. Circulation. Heart failure Maurer, M. S., Bokhari, S., Damy, T., Dorbala, S., Drachman, B. M., Fontana, M., Grogan, M., Kristen, A. V., Lousada, I., Nativi-Nicolau, J., Cristina Quarta, C., Rapezzi, C., Ruberg, F. L., Witteles, R., Merlini, G. 2019; 12 (9): e006075

    Abstract

    Cardiomyopathy is a manifestation of transthyretin amyloidosis (ATTR), which is an underrecognized systemic disease whereby the transthyretin protein misfolds to form fibrils that deposit in various tissues and organs. ATTR amyloidosis is debilitating and associated with poor life expectancy, especially in those with cardiac dysfunction, but a variety of treatment options have recently become available. Considered a rare disease, ATTR amyloidosis may be more prevalent than thought, particularly in older persons. Diagnosis is often delayed because of a lack of disease awareness and the heterogeneity of symptoms at presentation. Given the recent availability of effective treatments, early recognition and diagnosis are especially critical because treatment is likely more effective earlier in the disease course. The Amyloidosis Research Consortium recently convened a group of experts in ATTR amyloidosis who, through an iterative process, agreed on best practices for suspicion, diagnosis, and characterization of disease. This review describes these consensus recommendations for ATTR associated with cardiomyopathy as a resource to aid cardiologists and others in the recognition and diagnosis of ATTR associated with cardiomyopathy. Included in this review is an overview of red flag signs and symptoms and a recommended diagnostic approach, including testing for monoclonal protein, scintigraphy, or biopsy and, if ATTR associated with cardiomyopathy is identified, TTR genotyping.

    View details for DOI 10.1161/CIRCHEARTFAILURE.119.006075

    View details for PubMedID 31480867

  • Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy NEW ENGLAND JOURNAL OF MEDICINE Maurer, M. S., Schwartz, J. H., Gundapaneni, B., Elliott, P. M., Merlini, G., Waddington-Cruz, M., Kristen, A. V., Grogan, M., Witteles, R., Damy, T., Drachman, B. M., Shah, S. J., Hanna, M., Judge, D. P., Barsdorf, A. I., Huber, P., Patterson, T. A., Riley, S., Schumacher, J., Stewart, M., Sultan, M. B., Rapezzi, C., ATTR-ACT Study Investigators 2018; 379 (11): 1007–16
  • The State of Medical Student Performance Evaluations: Improved Transparency or Continued Obfuscation? Academic medicine Hom, J., Richman, I., Hall, P., Ahuja, N., Harman, S., Harrington, R., Witteles, R. 2016; 91 (11): 1534-1539

    Abstract

    The medical student performance evaluation (MSPE), a letter summarizing academic performance, is included in each medical student's residency application. The extent to which medical schools follow Association of American Medical Colleges (AAMC) recommendations for comparative and transparent data is not known. This study's purpose was to describe the content, interpretability, and transparency of MSPEs.This cross-sectional study examined one randomly selected MSPE from every Liaison Committee on Medical Education-accredited U.S. medical school from which at least one student applied to the Stanford University internal medical residency program during the 2013-2014 application cycle. The authors described the number, distribution, and range of key words and clerkship grades used in the MSPEs and the proportions of schools with missing or incomplete data.The sample included MSPEs from 117 (89%) of 131 medical schools. Sixty schools (51%) provided complete information about clerkship grade and key word distributions. Ninety-six (82%) provided comparative data for clerkship grades, and 71 (61%) provided complete key word data. Key words describing overall performance were extremely heterogeneous, with a total of 72 used and great variation in the assignment of the top designation (median: 24% of students; range: 1%-60%). There was also great variation in the proportion of students awarded the top internal medicine clerkship grade (median: 29%; range: 2%-90%).The MSPE is a critical component of residency applications, yet data contained within MSPEs are incomplete and variable. Approximately half of U.S. medical schools do not follow AAMC guidelines for MSPEs.

    View details for PubMedID 26703411

  • Changing outcomes after heart transplantation in patients with amyloid cardiomyopathy JOURNAL OF HEART AND LUNG TRANSPLANTATION Davis, M. K., Lee, P. H., Witteles, R. M. 2015; 34 (5): 658-666

    Abstract

    Amyloid cardiomyopathy (ACM) is associated with a poor prognosis. Previous reports have suggested unfavorable post-heart transplant (HT) survival in this population compared with other HT recipients.Data from the United Network for Organ Sharing (UNOS) registry were used to study outcomes among ACM patients undergoing HT in the modern era (Era 2, 2008 to 2013) as compared with the historical era (Era 1, 1987 to 2007).One hundred eighty-eight ACM patients underwent primary single-organ HT. Ninety-seven patients (51.6%) were transplanted in Era 1 and 91 (48.4%) in Era 2. ACM patients undergoing HT in Era 2 were older (p < 0.0001), had higher body mass index (p = 0.008) and longer ischemic times (p = 0.02), and were more likely to be African-American (p < 0.0001), UNOS Status 1A (p < 0.0001), male (p = 0.01) and highly sensitized (p < 0.0001) compared with those in Era 1. Compared with patients with other etiologies of restrictive cardiomyopathy (RCM; n = 339 in Era 1, n = 164 in Era 2), adjusted hazard ratios (HRs) for post-HT mortality of ACM were 2.08 (p < 0.0001) in Era 1 and 1.22 (p = not statistically significant) in Era 2. Adjusted HRs for mortality of ACM vs all other diagnoses (n = 36,334 in Era 1, n = 9,225 in Era 2) were 1.84 (p < 0.0001) in Era 1 and 1.38 (p = NS) in Era 2. Although post-HT survival did not change with time among non-ACM RCM patients, post-HT mortality was lower in Era 2 compared with Era 1 among ACM patients (HR 0.49, p = 0.03).Although historically associated with inferior survival, post-HT outcomes in ACM patients in the modern era are now approaching those of non-ACM patients. Changes in patients' demographics suggest that this may be related to improved patient selection, including an increased proportion of patients with transthyretin ACM. HT should be considered for appropriate candidates with ACM.

    View details for DOI 10.1016/j.healun.2014.09.006

    View details for PubMedID 25444369

  • Outcomes after heart transplantation for amyloid cardiomyopathy in the modern era. American journal of transplantation Davis, M. K., Kale, P., Liedtke, M., Schrier, S., Arai, S., Wheeler, M., Lafayette, R., Coakley, T., Witteles, R. M. 2015; 15 (3): 650-658

    Abstract

    We conducted a review of patients undergoing heart transplantation (HT) at our institution for amyloid cardiomyopathy (ACM) between 2008 and 2013. Complete follow-up was available for all patients. Nineteen patients with ACM underwent HT during the study period, accounting for 9.4% of all HT performed at our institution during this period. Amyloid subtype was light chain (AL) in 9 patients and transthyretin (ATTR) in 10 (2 wild-type, 7 familial, 1 unknown). Eight of nine patients with AL amyloidosis began chemotherapy prior to HT, six have resumed chemotherapy since HT, and five have undergone autologous stem cell transplantation. Most recent free light chain levels in AL patients decreased by a median of 85% from peak values. Only one patient developed recurrent graft amyloidosis, occurring at 3.5 years post-HT and asymptomatic. After a median follow-up of 380 days, 17 (89.5%) patients are alive. To our knowledge, this is the largest single-center series reported of ACM patients undergoing HT in the modern era. Our results suggest that acceptable outcomes following HT can be achieved in the short-to-intermediate term and that this is a feasible option for end-stage ACM with careful patient selection and aggressive control of amyloidogenic light chains in AL patients.

    View details for DOI 10.1111/ajt.13025

    View details for PubMedID 25648766

  • 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 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 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 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 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 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 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 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 PubMedID 15234411

  • Diagnosis and Treatment of Cardiac Amyloidosis Related to Plasma Cell Dyscrasias. Cardiology clinics Alexander, K. M., Evangelisti, A., Witteles, R. M. 2019; 37 (4): 487–95

    Abstract

    Light chain amyloidosis is a deadly disease in which a monoclonal plasma cell dyscrasia produces misfolded immunoglobulin light chains (AL) that aggregate and form rigid amyloid fibrils. The amyloid deposits infiltrate one or more organs, leading to injury and severe dysfunction. The degree of cardiac involvement is a major driver of morbidity and mortality. Early diagnosis and treatment are crucial to prevent irreversible end-organ damage and improve overall survival. Treatment of AL cardiac amyloidosis involves eliminating the underlying plasma cell dyscrasia with chemotherapy and pursuing supportive heart failure management.

    View details for DOI 10.1016/j.ccl.2019.07.013

    View details for PubMedID 31587789

  • Efficacy and Safety of Tafamidis Doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) Hanna, M., Damy, T., Garcia-Pavia, P., Judge, D. P., Merlini, G., Maurer, M. S., Gundapaneni, B., Patterson, T. A., Schwartz, J. H., Sultan, M. B., Witteles, R. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2019: S77–S78
  • Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Judge, D. P., Heitner, S. B., Falk, R. H., Maurer, M. S., Shah, S. J., Witteles, R. M., Grogan, M., Selby, V. N., Jacoby, D., Hanna, M., Nativi-Nicolau, J., Patel, J., Rao, S., Sinha, U., Turtle, C. W., Fox, J. C. 2019; 74 (3): 285–95
  • Grading cardiac response in AL amyloidosis: implications for relapse and survival BRITISH JOURNAL OF HAEMATOLOGY Eckhert, E., Witteles, R., Kaufman, G., Lafayette, R., Arai, S., Schrier, S., O'Shaughnessy, M., Liedtke, M. 2019; 186 (1): 144–46

    View details for DOI 10.1111/bjh.15717

    View details for Web of Science ID 000472576700020

  • Human-Induced Pluripotent Stem Cell Model of Trastuzumab-Induced Cardiac Dysfunction in Patients With Breast Cancer CIRCULATION Kitani, T., Ong, S., Lam, C., Rhee, J., Zhang, J. Z., Oikonomopoulos, A., Ma, N., Tian, L., Lee, J., Telli, M. L., Witteles, R. M., Sharma, A., Sayed, N., Wu, J. C. 2019; 139 (21): 2451–65
  • Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy. Journal of the American College of Cardiology Judge, D. P., Falk, R. H., Maurer, M. S., Shah, S. J., Witteles, R. M., Grogan, M., Selby, V. N., Jacoby, D., Hanna, M., Nativi-Nicolau, J., Patel, J., Rao, S., Sinha, U., Turtle, C. W., Fox, J. C., Heitner, S. B. 2019

    Abstract

    BACKGROUND: Transthyretin (TTR) amyloidosis (ATTR) is an under-diagnosed disease caused by destabilization of TTR due to pathogenic mutations or aging. Both pathogenic and protective mutations illuminate mechanisms of disease and potential interventions. AG10 is a selective, oral TTR stabilizer under development for ATTR cardiomyopathy (ATTR-CM) that mimics a protective TTR mutation.OBJECTIVES: This randomized, double-blind, placebo-controlled study evaluated safety, tolerability, pharmacokinetics and pharmacodynamics of AG10 in ATTR-CM patients with symptomatic, chronic heart failure.METHODS: ATTR-CM, NYHA Class II-III subjects (n = 49, mutant or wild-type) were randomized 1:1:1 to AG10 400mg, 800mg or placebo bid for 28 days. Safety and tolerability were assessed by clinical and laboratory criteria. AG10 plasma levels were measured. TTR stability was assessed by changes in serum TTR and two established ex vivo assays (Fluorescent Probe Exclusion [FPE] and Western blot).RESULTS: AG10 treatment was well-tolerated, achieved target plasma concentrations and demonstrated near-complete stabilization of TTR. TTR stabilization was more complete and less variable at the higher dose with stabilization by FPE of 92 ± 10% (mean±SD) at trough and 96 ± 9% at peak (both p<10-12 vs placebo). Average serum TTR increased by 36 ± 21% and 51 ± 38% at 400 mg and 800 mg respectively (both p<0.0001 vs placebo). Baseline serum TTR in treated subjects was below normal in 80% of mutant and 33% of wild-type subjects. AG10 treatment restored serum TTR to the normal range in all subjects.CONCLUSIONS: AG10 has the potential to be a safe and effective treatment for patients with ATTR-CM. A Phase 3 trial is planned.

    View details for PubMedID 30885685

  • Doxycycline and Ursodiol for ATTR Amyloidosis: Not Ready for Prime Time JOURNAL OF CARDIAC FAILURE Witteles, R. M. 2019; 25 (3): 154–55
  • REPLY: Increasingly Recognized Role of Right Ventricle Assessment in Cardiac Amyloidosis JACC-HEART FAILURE Amsallem, M., Witteles, R., Haddad, F. 2019; 7 (3): 279–80

    View details for DOI 10.1016/j.jchf.2018.12.010

    View details for Web of Science ID 000460037600017

    View details for PubMedID 30819389

  • Serial Cardiac FDG-PET for the Diagnosis and Therapeutic Guidance of Patients with Cardiac Sarcoidosis. Journal of cardiac failure Ning, N., Guo, H. H., Iagaru, A., Mittra, E., Fowler, M., Witteles, R. 2019

    Abstract

    BACKGROUND: Cardiac fluorodeoxyglucose positron emission tomography (FDG-PET) has emerged as a standard imaging modality for the diagnosis of cardiac sarcoidosis (CS); however, there is a scarcity of data on the use of serial FDG-PET to guide immunosuppressive therapy.OBJECTIVES: To report our experience in using serial FDG-PET for the diagnosis and management of patients with CS, focusing on its utility in ongoing immunosuppression management.METHODS: We studied consecutive patients with CS managed at Stanford University from 2010-2017. We evaluated our experience in using FDG-PET for diagnosis and guidance of immunosuppressive therapy titration in CS.RESULTS: Among 34 patients diagnosed with CS, 16 (47%), 12 (35%) and 14 (41%) patients presented with heart block, heart failure and ventricular arrhythmias, respectively. FDG-PET proved beneficial in the initial diagnosis in 21 (62%) patients. 128 FDG-PET scans were performed (median 3/patient). Ninety-four (73%) FDG-PET scans resulted in a change in therapy, with 42 (33%) FDG-PET scans instrumental for tapering prednisone. Among patients who were initiated on prednisone, the mean dose of prednisone at one year was 9.5 mg/day. Over a median follow-up of 2.3 years, 48% of patients were successfully weaned off of prednisone completely, and 20% were weaned to a maintenance dosage of 5-10 mg/day. During the follow-up period, transplant-free survival was 88%.CONCLUSIONS: The use of serial cardiac FDG-PET for the diagnosis and management of CS was critical for guiding immunosuppression management and resulted in low chronic steroid doses and good disease control within one year of diagnosis.

    View details for PubMedID 30825644

  • Doxycycline and Ursodiol for ATTR Amyloidosis: Not Ready for Prime Time. Journal of cardiac failure Witteles, R. 2019

    View details for PubMedID 30726714

  • Emerging Therapies for Transthyretin Cardiac Amyloidosis. Current treatment options in cardiovascular medicine Alexander, K. M., Evangelisti, A., Witteles, R. M. 2019; 21 (8): 40

    Abstract

    Transthyretin cardiac amyloidosis is an underdiagnosed, undertreated disease which is associated with significant morbidity and mortality. This review will discuss the recent advancements in novel therapies for transthyretin amyloidosis.In recent phase 3 clinical trials, transthyretin stabilizers (tafamidis) and transthyretin silencers (patisiran and inotersen) have proven to be effective therapies for various forms of transthyretin amyloidosis. Understanding the recent and upcoming clinical trials for transthyretin amyloidosis will be important for improving the management of this challenging disease.

    View details for DOI 10.1007/s11936-019-0743-2

    View details for PubMedID 31309347

  • Genomics in medicine: a novel elective rotation for internal medicine residents. Postgraduate medical journal Geng, L. N., Kohler, J. N., Levonian, P., Bernstein, J. A., Ford, J. M., Ahuja, N., Witteles, R., Hom, J., Wheeler, M. 2019

    Abstract

    It is well recognised that medical training globally and at all levels lacks sufficient incorporation of genetics and genomics education to keep up with the rapid advances and growing application of genomics to clinical care. However, the best strategy to implement these desired changes into postgraduate medical training and engage learners is still unclear. We developed a novel elective rotation in 'Genomic Medicine and Undiagnosed Diseases' for categorical Internal Medicine Residents to address this educational gap and serve as an adaptable model for training that can be applied broadly across different specialties and at other institutions. Key curriculum goals achieved include increased understanding about genetic testing modalities and tools available for diagnosis and risk analysis, the role of genetics-trained allied health professionals, and indications and limitations of genetic and genomic testing in both rare and common conditions.

    View details for DOI 10.1136/postgradmedj-2018-136355

    View details for PubMedID 31439813

  • Thrombophilia testing in the inpatient setting: impact of an educational intervention. BMC medical informatics and decision making Kwang, H., Mou, E., Richman, I., Kumar, A., Berube, C., Kaimal, R., Ahuja, N., Harman, S., Johnson, T., Shah, N., Witteles, R., Harrington, R., Shieh, L., Hom, J. 2019; 19 (1): 167

    Abstract

    Thrombophilia testing is frequently ordered in the inpatient setting despite its limited impact on clinical decision-making and unreliable results in the setting of acute thrombosis or ongoing anticoagulation. We sought to determine the effect of an educational intervention in reducing inappropriate thrombophilia testing for hospitalized patients.During the 2014 academic year, we implemented an educational intervention with a phase implementation design for Internal Medicine interns at Stanford University Hospital. The educational session covering epidemiology, appropriate thrombophilia evaluation and clinical rationale behind these recommendations. Their ordering behavior was compared with a contemporaneous control (non-medicine and private services) and a historical control (interns from prior academic year). From the analyzed data, we determined the proportion of inappropriate thrombophilia testing of each group. Logistic generalized estimating equations were used to estimate odds ratios for inappropriate thrombophilia testing associated with the intervention.Of 2151 orders included, 934 were deemed inappropriate (43.4%). The two intervention groups placed 147 orders. A pooled analysis of ordering practices by intervention groups revealed a trend toward reduction of inappropriate ordering (p = 0.053). By the end of the study, the intervention groups had significantly lower rates of inappropriate testing compared to historical or contemporaneous controls.A brief educational intervention was associated with a trend toward reduction in inappropriate thrombophilia testing. These findings suggest that focused education on thrombophilia testing can positively impact inpatient ordering practices.

    View details for DOI 10.1186/s12911-019-0889-6

    View details for PubMedID 31429747

  • Human Induced Pluripotent Stem Cell Model of Trastuzumab-Induced Cardiac Dysfunction in Breast Cancer Patients. Circulation Kitani, T., Ong, S. G., Lam, C. K., Rhee, J. W., Zhang, J. Z., Oikonomopoulos, A., Ma, N., Tian, L., Lee, J., Telli, M. L., Witteles, R. M., Sharma, A., Sayed, N., Wu, J. C. 2019

    Abstract

    Molecular targeted chemotherapies have been shown to significantly improve cancer patient outcomes, but often cause cardiovascular side effects that limit their use and impair patients' quality of life. Cardiac dysfunction induced by these therapies, especially trastuzumab, shows a distinct cardiotoxic clinical phenotype compared to cardiotoxicity induced by conventional chemotherapies.We employed the human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) platform to determine the underlying cellular mechanisms in trastuzumab-induced cardiac dysfunction. We assessed the effects of trastuzumab on structural and functional properties in iPSC-CMs from healthy individuals and performed RNA-sequencing (RNA-seq) to further examine the effect of trastuzumab on iPSC-CMs. We also generated iPSCs from patients receiving trastuzumab and examined whether patients' phenotype could be recapitulated in vitro using patient-specific iPSC-CMs.We found that clinically relevant doses of trastuzumab significantly impaired the contractile and calcium handling properties of iPSC-CMs without inducing cardiomyocyte death or sarcomeric disorganization. RNA-seq and subsequent functional analysis revealed mitochondrial dysfunction and altered cardiac energy metabolism pathway as primary causes of trastuzumab-induced cardiotoxic phenotype. Human iPSC-CMs generated from patients who received trastuzumab and experienced severe cardiac dysfunction were more vulnerable to trastuzumab treatment, compared to iPSC-CMs generated from patients who did not experience cardiac dysfunction following trastuzumab therapy. Importantly, metabolic modulation with AMPK activators could avert the adverse effects induced by trastuzumab.Our results indicate that alterations in cellular metabolic pathways in cardiomyocytes could be a key mechanism underlying the development of cardiac dysfunction following trastuzumab therapy; therefore, targeting the altered metabolism may be a promising therapeutic approach for trastuzumab-induced cardiac dysfunction.

    View details for PubMedID 30866650

  • Grading cardiac response in AL amyloidosis: implications for relapse and survival. British journal of haematology Eckhert, E., Witteles, R., Kaufman, G., Lafayette, R., Arai, S., Schrier, S., O'Shaughnessy, M., Liedtke, M. 2018

    View details for PubMedID 30569572

  • Safety, Tolerability and Transthyretin Stabilization by AG10: A Phase 2, Randomized, Double-blind, Placebo-controlled Clinical Trial in Patients with Transthyretin Amyloid Cardiomyopathy and NYHA Class II/III Heart Failure Judge, D. P., Falk, R., Grogan, M., Heitner, S. B., Jacoby, D., Maurer, M., Selby, V. N., Shah, S. J., Witteles, R. M., Hanna, M., Patel, J., Nativi-Nicolau, J., Rao, S., Sinha, U., Fox, J. C. LIPPINCOTT WILLIAMS & WILKINS. 2018: E770
  • Graded Cardiac Response Correlates with Relapse and Survival in AL Amyloidosis Eckhert, E., Witteles, R., Kaufman, G., Lafayette, R., Arai, S., Schrier, S., O'Shaughnessy, M., Liedtke, M. AMER SOC HEMATOLOGY. 2018
  • Efficacy of Tafamidis in Transthyretin Amyloid Cardiomyopathy in the ATTR-ACT Trial: Sensitivity Analyses Further Support the Primary Results Maurer, M. S., Schwartz, J. H., Gundapaneni, B., Elliott, P., Merlini, G., Cruz, M., Kristen, A. V., Grogan, M., Witteles, R., Damy, T., Drachman, B. M., Shah, S. J., Hanna, M., Judge, D. P., Gottlieb, S. S., Berk, J. L., Lenihan, D. J., Hoffman, J. E., Hummel, S. L., Velazquez, E. J., Patterson, T. A., Sultan, M. B., Rapezzi, C. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2018: 813
  • Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. The New England journal of medicine Maurer, M. S., Schwartz, J. H., Gundapaneni, B., Elliott, P. M., Merlini, G., Waddington-Cruz, M., Kristen, A. V., Grogan, M., Witteles, R., Damy, T., Drachman, B. M., Shah, S. J., Hanna, M., Judge, D. P., Barsdorf, A. I., Huber, P., Patterson, T. A., Riley, S., Schumacher, J., Stewart, M., Sultan, M. B., Rapezzi, C., ATTR-ACT Study Investigators 2018

    Abstract

    Background Transthyretin amyloid cardiomyopathy is caused by the deposition of transthyretin amyloid fibrils in the myocardium. The deposition occurs when wild-type or variant transthyretin becomes unstable and misfolds. Tafamidis binds to transthyretin, preventing tetramer dissociation and amyloidogenesis. Methods In a multicenter, international, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 441 patients with transthyretin amyloid cardiomyopathy in a 2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis, or placebo for 30 months. In the primary analysis, we hierarchically assessed all-cause mortality, followed by frequency of cardiovascular-related hospitalizations according to the Finkelstein-Schoenfeld method. Key secondary end points were the change from baseline to month 30 for the 6-minute walk test and the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS), in which higher scores indicate better health status. Results In the primary analysis, all-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received tafamidis than among the 177 patients who received placebo (P<0.001). Tafamidis was associated with lower all-cause mortality than placebo (78 of 264 [29.5%] vs. 76 of 177 [42.9%]; hazard ratio, 0.70; 95% confidence interval [CI], 0.51 to 0.96) and a lower rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68 (0.48 per year vs. 0.70 per year; 95% CI, 0.56 to 0.81). At month 30, tafamidis was also associated with a lower rate of decline in distance for the 6-minute walk test (P<0.001) and a lower rate of decline in KCCQ-OS score (P<0.001). The incidence and types of adverse events were similar in the two groups. Conclusions In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo. (Funded by Pfizer; ATTR-ACT ClinicalTrials.gov number, NCT01994889 .).

    View details for PubMedID 30145929

  • 18F-florbetaben whole-body PET/MRI for evaluation of systemic amyloid deposition. EJNMMI research Baratto, L., Park, S. Y., Hatami, N., Gulaka, P., Vasanawala, S., Yohannan, T. K., Herfkens, R., Witteles, R., Iagaru, A. 2018; 8 (1): 66

    Abstract

    BACKGROUND: Florbetaben, a 18F-labeled stilbene derivative (Neuraceq, formerly known as BAY-949172), is a diagnostic radiopharmaceutical developed to visualize beta-amyloid plaques in the brain. Here, we report a pilot study evaluating patients with suspected cardiac amyloidosis for systemic extent of disease.METHODS: We prospectively enrolled nine patients, 61-86year old (mean±SD 69.4±8.6), referred from the cardiac amyloid clinic. First, dynamic imaging of the heart was acquired immediately after injection of 222-318.2MBq (mean±SD 270.1±33.3) of 18F-florbetaben using the GE SIGNA PET/MRI. This was followed by a whole-body PET/MRI scan 60-146.4min (mean±SD 98±33.4) after injection. Cardiac MRI sequences included ECG-triggered cine SSFP, T2-weighted, and late gadolinium-enhanced imaging. Whole-body MRI sequences included MRAC and axial T1-weighted imaging.RESULTS: High early uptake and delayed high uptake in the left ventricle correlated with amyloid deposition in five patients, while low uptake on early and delayed cardiac imaging was noted in four patients. Cardiac function measurements were successfully obtained in all participants. Areas of increased abnormal 18F-florbetaben accumulation were noted on delayed whole-body imaging in the bone marrow (seven patients), stomach (diffuse in five patients and focal in one patient), brain (five patients), salivary glands (three patients), tongue (three patients), spleen (three patients), skeletal muscles (three patients), ocular muscles (two patients), thyroid (two patients), pleura (two patients), kidneys (two patients), and lungs (two patients).CONCLUSIONS: Whole-body 18F-florbetaben PET/MRI is promising for localization of systemic amyloid deposition. This technique may provide important structural and functional information regarding the organs involved by disease, with potential to guide biopsy and evaluate response to treatment.TRIAL REGISTRATION: Clinicaltrials.gov registration: NCT03119558 .

    View details for PubMedID 30043115

  • F-18-florbetaben whole-body PET/MRI for evaluation of systemic amyloid deposition EJNMMI RESEARCH Baratto, L., Park, S., Hatami, N., Gulaka, P., Vasanawala, S., Yohannan, T., Herfkens, R., Witteles, R., Iagaru, A. 2018; 8
  • SERIAL CARDIAC FDG-PET IN THE DIAGNOSIS AND THERAPEUTIC GUIDANCE OF PATIENTS WITH CARDIAC SARCOIDOSIS: A STANFORD EXPERIENCE Ning, N., Guo, H. H., Jagaru, A., Mittra, E., Fowler, M., Witteles, R. ELSEVIER SCIENCE INC. 2018: 1690
  • Atrial Septal Defect as Unexpected Cause of Pulmonary Artery Hypertension TEXAS HEART INSTITUTE JOURNAL Parikh, R., Boyd, J., Lee, D. P., Witteles, R. 2018; 45 (1): 42–44

    Abstract

    Methamphetamine abuse is an increasingly prevalent cause of pulmonary artery hypertension in the United States. Conversely, an atrial septal defect rarely presents late as pulmonary artery hypertension. We present the case of a 44-year-old methamphetamine abuser who had a 3-month history of worsening fatigue and near-syncope. She had elevated cardiac enzyme levels and right-sided heart strain. Angiographic findings suggested methamphetamine-induced pulmonary artery hypertension; however, we later heard S2 irregularities that raised suspicion of an atrial septal defect. Ultimately, the diagnosis was pulmonary artery hypertension and a large secundum atrial septal defect with left-to-right flow. One year after defect closure, the patient was asymptomatic. In addition to discussing this unexpected case of a secundum atrial septal defect masquerading as methamphetamine-induced pulmonary artery hypertension, we briefly review the natural history of atrial septal defects and emphasize the importance of thorough examination in avoiding diagnostic anchoring bias.

    View details for DOI 10.14503/THIJ-17-6208

    View details for Web of Science ID 000426402700011

    View details for PubMedID 29556152

    View details for PubMedCentralID PMC5832086

  • A high value care curriculum for interns: a description of curricular design, implementation and housestaff feedback POSTGRADUATE MEDICAL JOURNAL Hom, J., Kumar, A., Evans, K. H., Svec, D., Richman, I., Fang, D., Smeraglio, A., Holubar, M., Johnson, T., Shah, N., Renault, C., Ahuja, N., Witteles, R., Harman, S., Shieh, L. 2017; 93 (1106): 725–29
  • Carcinoid Syndrome Complicating a Pancreatic Neuroendocrine Tumor A Case Report PANCREAS Gerson, J. N., Witteles, R. M., Chang, D. T., Beygui, R. E., Iagaru, A. H., Kunz, P. L. 2017; 46 (10): 1381–85

    Abstract

    Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms. These tumors can produce a wide variety of hormones that can lead to syndromes of hormone excess, such as carcinoid syndrome. We present the case of a 47-year-old man who presented with right upper quadrant abdominal pain and emesis. He was found to have metastatic pancreatic NET and was treated with systemic chemotherapy. He subsequently developed dyspnea on exertion and was found to have severe right-sided heart disease secondary to elevated levels of serum serotonin. He was successfully treated with surgical tricuspid and pulmonic valve replacement. True carcinoid syndrome with pancreatic NETs is rare, but, as a treatable complication of the disease, is an important entity for which oncologists should be familiar.

    View details for PubMedID 29040196

  • Epidemiology and Clinical Implications of Gastrointestinal Symptoms in Systemic Amyloidosis Yen, T., Chen, F., Witteles, R., Liedtke, M., Nguyen, L. NATURE PUBLISHING GROUP. 2017: S240
  • Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis BLOOD Kaufman, G. P., Schrier, S. L., Lafayette, R. A., Arai, S., Witteles, R. M., Liedtke, M. 2017; 130 (7): 900–902

    Abstract

    The majority of patients with immunoglobulin light chain amyloidosis (AL) fail to achieve a complete response (CR) to standard light chain suppressive chemotherapy, and almost all patients eventually experience hematologic relapse and progression of organ involvement. Additional well-tolerated treatment options are needed. We present our retrospective experience of 25 consecutive previously treated AL patients who received daratumumab, a CD38-directed monoclonal antibody approved for the treatment of multiple myeloma. Daratumumab was administered at 16 mg/kg weekly for 8 weeks, then every 2 weeks for 8 doses, and then every 4 weeks. Patients had received a median of 3 prior lines of therapy, with a previous hematologic CR in only 5 patients. The overall hematologic response rate to daratumumab was 76%, including CR in 36% and very good partial response in 24%. Median time to response was 1 month. Therapy was well tolerated, even among the 72% of patients with cardiac AL involvement. Grade 1-2 infusion reactions occurred in 15 patients, but no grade 3 or 4 reactions were observed. Daratumumab is a highly effective agent that produced rapid and deep hematologic responses without unexpected toxicity in our cohort of heavily pretreated AL patients.

    View details for PubMedID 28615223

  • WHOLE HEART OF THE MATTER Parikh, R., Boyd, J., Lee, D., Witteles, R. ELSEVIER SCIENCE INC. 2017: 2411
  • A high value care curriculum for interns: a description of curricular design, implementation and housestaff feedback. Postgraduate medical journal Hom, J., Kumar, A., Evans, K. H., Svec, D., Richman, I., Fang, D., Smeraglio, A., Holubar, M., Johnson, T., Shah, N., Renault, C., Ahuja, N., Witteles, R., Harman, S., Shieh, L. 2017

    Abstract

    Most residency programmes do not have a formal high value care curriculum. Our goal was to design and implement a multidisciplinary high value care curriculum specifically targeted at interns.Our curriculum was designed with multidisciplinary input from attendings, fellows and residents at Stanford. Curricular topics were inspired by the American Board of Internal Medicine's Choosing Wisely campaign, Alliance for Academic Internal Medicine, American College of Physicians and Society of Hospital Medicine. Our topics were as follows: introduction to value-based care; telemetry utilisation; lab ordering; optimal approach to thrombophilia work-ups and fresh frozen plasma use; optimal approach to palliative care referrals; antibiotic stewardship; and optimal approach to imaging for low back pain. Our curriculum was implemented at the Stanford Internal Medicine residency programme over the course of two academic years (2014 and 2015), during which 100 interns participated in our high value care curriculum. After each high value care session, interns were offered the opportunity to complete surveys regarding feedback on the curriculum, self-reported improvements in knowledge, skills and attitudinal module objectives, and quiz-based knowledge assessments.The overall survey response rate was 67.1%. Overall, the material was rated as highly useful on a 5-point Likert scale (mean 4.4, SD 0.6). On average, interns reported a significant improvement in their self-rated knowledge, skills and attitudes after the six seminars (mean improvement 1.6 points, SD 0.4 (95% CI 1.5 to 1.7), p<0.001).We successfully implemented a novel high value care curriculum that specifically targets intern physicians.

    View details for PubMedID 28663352

  • Functional Cardiac Recovery and Hematologic Response to Chemotherapy in Patients With Light-Chain Amyloidosis (from the Stanford University Amyloidosis Registry). The American journal of cardiology Tuzovic, M., Kobayashi, Y., Wheeler, M., Barrett, C., Liedtke, M., Lafayette, R., Schrier, S., Haddad, F., Witteles, R. 2017; 120 (8): 1381–86

    Abstract

    Cardiac involvement is common in patients with light-chain (AL) amyloidosis and portends a poor prognosis, although little is known about the changes in cardiac mechanics after chemotherapy. We sought to explore the relation between amyloidosis staging and baseline cardiac mechanics and to investigate short-term changes in cardiac mechanics after chemotherapy. We identified 41 consecutive patients from the Stanford Amyloid Center who had echocardiograms and free light-chain values before and after chemotherapy, along with 40 age- and gender-matched controls. Echocardiographic assessment included left ventricular global longitudinal strain, E/e' ratio, and left atrial (LA) stiffness. Hematologic response to chemotherapy was defined as ≥50% reduction in the difference between the involved and the uninvolved free light chain (dFLC). The mean age was 66.9 ± 8.4 years and 66% were men. Before chemotherapy, global longitudinal strain, E/e' ratio, and LA stiffness were impaired in patients with amyloidosis compared with controls, and the severity of impairment worsened with advanced staging. After chemotherapy, hematologic response was observed in 30 (73%) patients. There was a significant association between the change in dFLC and cardiac function (E/e' ratio: r = -0.43, p = 0.01; LA stiffness: r = -0.35, p = 0.05). There was no significant improvement in cardiac mechanics in patients without a hematologic response to chemotherapy. In conclusion, amyloidosis stage correlated with noninvasive measurements of cardiac mechanics, and improvement in dFLC correlated with cardiac improvement on short-term follow-up echocardiography.

    View details for PubMedID 28844519

  • A 15-year review of the Stanford Internal Medicine Residency Program: predictors of resident satisfaction and dissatisfaction ADVANCES IN MEDICAL EDUCATION AND PRACTICE Kahn, J. S., Witteles, R. M., Mahaffey, K. W., Desai, S. A., Ozdalga, E., Heidenreich, P. A. 2017; 8: 559–66

    Abstract

    Satisfaction with training and with educational experiences represents important internal medicine (IM) programmatic goals. Graduates from IM residency programs are uniquely poised to provide insights into their educational and training experiences and to assess whether these experiences were satisfactory and relevant to their current employment.We surveyed former IM residents from the training program held during the years 2000-2015 at the Department of Medicine, Stanford University. The first part of the survey reviewed the IM residency program and the second part sought identifying data regarding gender, race, ethnicity, work, relationships, and financial matters. The primary outcome was satisfaction with the residency experience.Of the 405 individuals who completed the Stanford IM residency program in the study period, we identified 384 (95%) former residents with a known email address. Two hundred and one (52%) former residents responded to the first part and 185 (48%) answered both the parts of the survey. The mean age of the respondents was 36.9 years; 44% were female and the mean time from IM residency was 6.1 (±4.3) years. Fifty-eight percent reported extreme satisfaction with their IM residency experience. Predictors associated with being less than extremely satisfied included insufficient outpatient experience, insufficient international experience, insufficient clinical research experience, and insufficient time spent with family and peers.The residents expressed an overall high satisfaction rate with their IM training. The survey results provided insights for improving satisfaction with IM residency training that includes diversifying and broadening IM training experiences.

    View details for PubMedID 28814910

  • Hematologic Responses and Cardiac Organ Improvement in Patients with Heavily Pretreated Cardiac Immunoglobulin Light Chain (AL) Amyloidosis Receiving Daratumumab Kaufman, G., Witteles, R., Wheeler, M., Ulloa, P., Lugtu, M., Arai, S., Schrier, S., Lafayette, R., Liedtke, M. AMER SOC HEMATOLOGY. 2016
  • Prevalence and Financial Impact of Inappropriate Thrombophilia Testing in the Inpatient Hospital Setting: A Retrospective Analysis Mou, E., Kwang, H., Hom, J., Shieh, L., Ahuja, N., Harman, S., Johnson, T., Kumar, A., Shah, N., Witteles, R., Berube, C. AMER SOC HEMATOLOGY. 2016
  • Accreditation Council for Graduate Medical Education (ACGME) Milestones-Time for a Revolt? JAMA internal medicine Witteles, R. M., Verghese, A. 2016; 176 (11): 1599-1600

    View details for DOI 10.1001/jamainternmed.2016.5552

    View details for PubMedID 27668812

  • The State of Medical Student Performance Evaluations: Improved Transparency or Continued Obfuscation? ACADEMIC MEDICINE Hom, J., Richman, I., Hall, P., Ahuja, N., Harman, S., Harrington, R., Witteles, R. 2016; 91 (11): 1534–39
  • A resident-created hospitalist curriculum for internal medicine housestaff. Journal of hospital medicine Kumar, A., Smeraglio, A., Witteles, R., Harman, S., Nallamshetty, S., Rogers, A., Harrington, R., Ahuja, N. 2016; 11 (9): 646-649

    Abstract

    The growth of hospital medicine has led to new challenges, and recent graduates may feel unprepared to meet the expanding clinical duties expected of hospitalists. At our institution, we created a resident-inspired hospitalist curriculum to address the training needs for the next generation of hospitalists. Our program provided 3 tiers of training: (1) clinical excellence through improved training in underemphasized areas of hospital medicine, (2) academic development through required research, quality improvement, and medical student teaching, and (3) career mentorship. In this article, we describe the genesis of our program, our final product, and the challenges of creating a curriculum while being internal medicine residents. Journal of Hospital Medicine 2016. © 2016 Society of Hospital Medicine.

    View details for DOI 10.1002/jhm.2590

    View details for PubMedID 27079160

  • Patient Outcomes when Housestaff Exceed 80 Hours per Week. American journal of medicine Ouyang, D., Chen, J. H., Krishnan, G., Hom, J., Witteles, R., Chi, J. 2016; 129 (9): 993-999 e1

    Abstract

    It has been posited that high workload and long work hours for trainees could affect the quality and efficiency of patient care. Duty hour restrictions seek to balance patient care and resident education by limiting resident work hours. Through a retrospective cohort study, we investigate whether patient care on an inpatient general medicine service at a large academic medical center is impacted when housestaff work greater than eighty hours per week METHODS: We identified all admissions to a housestaff-run general medicine service between June 25, 2013 and June 29, 2014. Each hospitalization was classified by whether or not the patient was admitted by housestaff who have worked more than eighty hours a week during their hospitalization. Housestaff computer activity and duty hours were calculated by institutional electronic heath record audit, as well as length of stay and a composite of in-hospital mortality, ICU transfer rate, and 30-day readmission rate.We identified 4,767 hospitalizations by 3,450 unique patients; of which 40.9% of hospitalizations were managed by housestaff who worked more than eighty hours that week during their hospitalization. There was a significantly higher rate of the composite outcome (19.2% vs. 16.7%, p = 0.031) for patients admitted by housestaff working more than eighty hours a week during their hospitalization. We found a statistically significant higher length of stay (5.12 vs. 4.66 days, p = 0.048) and rate of ICU transfer (3.18% vs. 2.38%, p = 0.029). There was no statistically significant difference in 30-day readmission rate (13.7% vs. 12.8%, p = 0.395), or in-hospital mortality rate (3.18% vs. 2.42%, p = 0.115).There was no correlation with team census on admission and patient outcomes.Patients taken care of by housestaff working more than eighty hours a week had increased length of stay and number of ICU transfers. There was no association between resident work-hours and patient in-hospital mortality or 30-day readmission rate.

    View details for DOI 10.1016/j.amjmed.2016.03.023

    View details for PubMedID 27103047

  • Genotype and Phenotype of Transthyretin Cardiac Amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). Journal of the American College of Cardiology Maurer, M. S., Hanna, M., Grogan, M., Dispenzieri, A., Witteles, R., Drachman, B., Judge, D. P., Lenihan, D. J., Gottlieb, S. S., Shah, S. J., Steidley, D. E., Ventura, H., Murali, S., Silver, M. A., Jacoby, D., Fedson, S., Hummel, S. L., Kristen, A. V., Damy, T., Planté-Bordeneuve, V., Coelho, T., Mundayat, R., Suhr, O. B., Waddington Cruz, M., Rapezzi, C. 2016; 68 (2): 161-172

    Abstract

    Transthyretin amyloidosis (ATTR) is a heterogeneous disorder with multiorgan involvement and a genetic or nongenetic basis.The goal of this study was to describe ATTR in the United States by using data from the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry.Demographic, clinical, and genetic features of patients enrolled in the THAOS registry in the United States (n = 390) were compared with data from patients from other regions of the world (ROW) (n = 2,140). The focus was on the phenotypic expression and survival in the majority of U.S. subjects with valine-to-isoleucine substitution at position 122 (Val122Ile) (n = 91) and wild-type ATTR (n = 189).U.S. subjects are older (70 vs. 46 years), more often male (85.4% vs. 50.6%), and more often of African descent (25.4% vs. 0.5%) than the ROW. A significantly higher percentage of U.S. patients with ATTR amyloid seen at cardiology sites had wild-type disease than the ROW (50.5% vs. 26.2%). In the United States, 34 different mutations (n = 201) have been reported, with the most common being Val122Ile (n = 91; 45.3%) and Thr60Ala (n = 41; 20.4%). Overall, 91 (85%) of 107 patients with Val122Ile were from the United States, where Val122Ile subjects were younger and more often female and black than patients with wild-type disease, and had similar cardiac phenotype but a greater burden of neurologic symptoms (pain, numbness, tingling, and walking disability) and worse quality of life. Advancing age and lower mean arterial pressure, but not the presence of a transthyretin mutation, were independently associated with higher mortality from a multivariate analysis of survival.In the THAOS registry, ATTR in the United States is overwhelmingly a disorder of older adult male subjects with a cardiac-predominant phenotype. Val122Ile is the most common transthyretin mutation, and neurologic phenotypic expression differs between wild-type disease and Val122Ile, but survival from enrollment in THAOS does not. (Transthyretin-Associated Amyloidoses Outcome Survey [THAOS]; NCT00628745).

    View details for DOI 10.1016/j.jacc.2016.03.596

    View details for PubMedID 27386769

    View details for PubMedCentralID PMC4940135

  • Genotype and Phenotype of Transthyretin Cardiac Amyloidosis THAOS (Transthyretin Amyloid Outcome Survey) JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Maurer, M. S., Hanna, M., Grogan, M., Dispenzieri, A., Witteles, R., Drachman, B., Judge, D. P., Lenihan, D. J., Gottlieb, S. S., Shah, S. J., Steidley, D. E., Ventura, H., Murali, S., Silver, M. A., Jacoby, D., Fedson, S., Hummel, S. L., Kristen, A. V., Damy, T., Plante-Bordeneuve, V., Coelho, T., Mundayat, R., Suhr, O. B., Cruz, M. W., Rapezzi, C. 2016; 68 (2): 161-172

    Abstract

    Transthyretin amyloidosis (ATTR) is a heterogeneous disorder with multiorgan involvement and a genetic or nongenetic basis.The goal of this study was to describe ATTR in the United States by using data from the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry.Demographic, clinical, and genetic features of patients enrolled in the THAOS registry in the United States (n = 390) were compared with data from patients from other regions of the world (ROW) (n = 2,140). The focus was on the phenotypic expression and survival in the majority of U.S. subjects with valine-to-isoleucine substitution at position 122 (Val122Ile) (n = 91) and wild-type ATTR (n = 189).U.S. subjects are older (70 vs. 46 years), more often male (85.4% vs. 50.6%), and more often of African descent (25.4% vs. 0.5%) than the ROW. A significantly higher percentage of U.S. patients with ATTR amyloid seen at cardiology sites had wild-type disease than the ROW (50.5% vs. 26.2%). In the United States, 34 different mutations (n = 201) have been reported, with the most common being Val122Ile (n = 91; 45.3%) and Thr60Ala (n = 41; 20.4%). Overall, 91 (85%) of 107 patients with Val122Ile were from the United States, where Val122Ile subjects were younger and more often female and black than patients with wild-type disease, and had similar cardiac phenotype but a greater burden of neurologic symptoms (pain, numbness, tingling, and walking disability) and worse quality of life. Advancing age and lower mean arterial pressure, but not the presence of a transthyretin mutation, were independently associated with higher mortality from a multivariate analysis of survival.In the THAOS registry, ATTR in the United States is overwhelmingly a disorder of older adult male subjects with a cardiac-predominant phenotype. Val122Ile is the most common transthyretin mutation, and neurologic phenotypic expression differs between wild-type disease and Val122Ile, but survival from enrollment in THAOS does not. (Transthyretin-Associated Amyloidoses Outcome Survey [THAOS]; NCT00628745).

    View details for DOI 10.1016/j.jacc.2016.03.596

    View details for Web of Science ID 000379123800005

    View details for PubMedCentralID PMC4940135

  • Biomarkers as Predictors of Cardiac Toxicity From Targeted Cancer Therapies JOURNAL OF CARDIAC FAILURE Witteles, R. M. 2016; 22 (6): 459-464

    Abstract

    Cardiac biomarkers have been extensively investigated as early detectors of cardiac toxicity from cancer therapies. Whereas the role of biomarkers in monitoring anthracycline toxicity is generally well understood, substantial uncertainty remains regarding their role in monitoring newer targeted cancer therapies.This review article examines all major published studies using cardiac troponins and/or N-terminal pro-B-type natriuretic peptide (NT-proBNP) in monitoring for cardiac toxicity with trastuzumab, tyrosine kinase inhibitors, and mammalian target of rapamycin (mTOR) inhibitors. There is substantial variability among studies regarding biomarker assays used, sensitivity of the assays, and definitions of abnormal results. In general, troponin I predicts early but not late cardiac events when trastuzumab is administered after anthracyclines, but troponin increases likely reflect anthracycline injury rather than trastuzumab injury. NT-proBNP detects cardiac toxicity with tyrosine kinase inhibitors and mTOR inhibitors, but not independently from echocardiography.Troponin I can serve as a marker for susceptibility to cardiac toxicity during early trastuzumab treatment in patients who have received recent anthracyclines. NT-proBNP can serve as a useful marker of cardiac toxicity in patients treated with tyrosine kinase inhibitors or mTOR inhibitors if echocardiographic screening is not being used.

    View details for DOI 10.1016/j.cardfail.2016.03.016

    View details for PubMedID 27038641

  • Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity NATURE MEDICINE Burridge, P. W., Li, Y. F., Matsa, E., Wu, H., Ong, S., Sharma, A., Holmstrom, A., Chang, A. C., Coronado, M. J., Ebert, A. D., Knowles, J. W., Telli, M. L., Witteles, R. M., Blau, H. M., Bernstein, D., Altman, R. B., Wu, J. C. 2016; 22 (5): 547-556

    Abstract

    Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but it causes a dose-related cardiotoxicity that can lead to heart failure in a subset of patients. At present, it is not possible to predict which patients will be affected by doxorubicin-induced cardiotoxicity (DIC). Here we demonstrate that patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can recapitulate the predilection to DIC of individual patients at the cellular level. hiPSC-CMs derived from individuals with breast cancer who experienced DIC were consistently more sensitive to doxorubicin toxicity than hiPSC-CMs from patients who did not experience DIC, with decreased cell viability, impaired mitochondrial and metabolic function, impaired calcium handling, decreased antioxidant pathway activity, and increased reactive oxygen species production. Taken together, our data indicate that hiPSC-CMs are a suitable platform to identify and characterize the genetic basis and molecular mechanisms of DIC.

    View details for DOI 10.1038/nm.4087

    View details for PubMedID 27089514

  • Response to Letter Regarding Article, "Myocardial Protection During Cardiotoxic Chemotherapy" CIRCULATION Witteles, R. M., Bosch, X. 2016; 133 (15): E598

    View details for PubMedID 27067094

  • Myocardial Protection During Cardiotoxic Chemotherapy CIRCULATION Witteles, R. M., Bosch, X. 2015; 132 (19): 1835–45

    View details for PubMedID 26553713

  • FROM PALPITATIONS TO CARDIOVASCULAR COLLAPSE: THE STORY OF A PHEOCHROMOCYTOMA Flint, K. M., Witteles, R. ELSEVIER SCIENCE INC. 2015: A618
  • Radiation-induced heart disease: an under-recognized entity? Current treatment options in cardiovascular medicine Davis, M., Witteles, R. M. 2014; 16 (6): 317-?

    Abstract

    Radiation-induced heart disease (RIHD) represents a spectrum of cardiovascular disease in patients who have undergone mediastinal, thoracic, or breast radiotherapy (RT). RIHD may involve any cardiac structure and is a major cause of morbidity and mortality in cancer survivors. While large cohort studies have demonstrated that symptomatic RIHD is a common late finding in this population, the incidence of asymptomatic disease is likely to be even higher. Long-term follow-up with regular screening for RIHD plays an important role in the management of cancer survivors who have undergone RT. Aggressive modification of traditional cardiovascular risk factors such as hypertension, dyslipidemia, and cigarette smoking is essential in patients at risk for RIHD, as these have been shown to potentiate the risks of radiation. In patients with symptomatic RIHD, medical and/or percutaneous therapies are often preferable to surgical interventions in view of the increased surgical risk associated with radiation damage to surrounding tissues. Percutaneous revascularization should generally be favored over surgical revascularization. Transcatheter valve replacements have not been widely used in this population but may offer an alternative to high-risk surgical valve procedures. Pericardiectomy is usually associated with extremely poor short-term and long-term outcomes in patients with RIHD and should be avoided in most cases. Heart transplantation is also higher risk in patients with RIHD than in patients with other etiologies of heart failure, but may be considered in young patients without other comorbidities.

    View details for DOI 10.1007/s11936-014-0317-2

    View details for PubMedID 24756471

  • Reply to "heart failure and breast cancer: emerging controversies regarding some cardioprotective strategies". Journal of cardiac failure Witteles, R. M., Thakur, A. 2014; 20 (6): 457-?

    View details for DOI 10.1016/j.cardfail.2014.04.015

    View details for PubMedID 24747785

  • Cancer therapy-induced left ventricular dysfunction: interventions and prognosis. Journal of cardiac failure Thakur, A., Witteles, R. M. 2014; 20 (3): 155-158

    Abstract

    For multiple chemotherapeutics, cardiotoxicity is dose limiting and can lead to substantial morbidity and mortality. Early cardiac intervention has the potential to positively affect clinical course.We reviewed 247 consecutive patients referred to the Stanford cardiology clinic for cancer therapy-associated cardiac abnormalities from 2004 to 2012. A comprehensive review of records was performed, with documentation of baseline characteristics, cardiac imaging, medications, and clinical course. Seventy-nine patients who had left ventricular ejection fraction (LVEF) declines temporally associated with cancer therapy were included. The most common malignancies were breast (46%) and hematologic (35%); 71% of the patients were female, and overall mean age was 52 years. The primary cancer therapeutics associated with LVEF decline included anthracyclines, trastuzumab, and tyrosine kinase inhibitors. The mean LVEF was 60% before cancer therapy and 40% after cancer therapy. The most common cardiac interventions included beta-blockers (84%) and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (83%). Mean LVEF after cardiac intervention rose to 53%; 77% of patients had LVEF recovery to ≥50%, and 68% of these patients had recovery within 6 months of starting cardiac therapy; 76% of patients were able to continue their planned cancer therapy.With appropriate cardiac intervention, the majority of patients with LVEF decline from cancer therapy can achieve LVEF recovery and complete their cancer therapy.

    View details for DOI 10.1016/j.cardfail.2013.12.018

    View details for PubMedID 24378722

  • 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

  • Chemotherapy-Induced Left Ventricular Dysfunction: Interventions and Prognosis Thakur, A., Witteles, R. M. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2013: S86–S87
  • 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

  • Development of a reproducible FDG PET/CT cardiac imaging protocol for the evaluation of cardiac sarcoidosis Kulm, J., Mittra, E., Guo, H., Witteles, R., Quon, A. SOC NUCLEAR MEDICINE INC. 2013
  • 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 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 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

  • 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 Web of Science ID 000209535300010

  • 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 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 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 PubMedID 23040117

  • Therapy With a DPP-4 Inhibitor Increases Myocardial Glucose Uptake in Nonischemic Cardiomyopathy Witteles, R. M., Keu, K. V., Quon, A., Tavana, H., Fowler, M. B. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2012: S10
  • Incidence and severity of cardiotoxicity in metastatic renal cell carcinoma (RCC) patients treated with targeted therapies. 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Hall, P. S., Witteles, R., Srinivas, S., Harshman, L. C. AMER SOC CLINICAL ONCOLOGY. 2012
  • 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 PubMedID 22652951

  • Cardiac Amyloidosis: Screening Criteria for Heart Transplantation and New Strategies for Post-Transplant Therapy 15th Annual Scientific Meeting of the Heart-Failure-Society-of-America Varr, B. C., Liedtke, M., Arai, S., Lafayette, R. A., Schrier, S. L., Witteles, R. M. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2011: S45–S46
  • Treating Asymptomatic Chemotherapy-Induced Cardiac Dysfunction A Chance That Cardiologists and Oncologists Should Not Miss Reply JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Witteles, R. M., Yoon, G., Telli, M., Kao, D. P., Matsuda, K. Y., Carlson, R. W. 2011; 57 (17): 1790-1791
  • OVERUSE OF LEFT VENTRICULOGRAPHY 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 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
  • 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 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

  • AL Amyloidosis and Concomitant Myeloma: Time to Reconsider Assumptions. Witteles, W., Witteles, R., Liedtke, M., Arai, S., Lafayette, R., George, T. I., Schrier, S. L. AMER SOC HEMATOLOGY. 2010: 1649
  • A Pilot Study of Melphalan, Lenalidomide and Dexamethasone In AL Amyloidosis: Interim Results 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Afghahi, A., Witteles, W., Witteles, R., Liedtke, M., Lafayette, R., Arai, S., Schrier, S. L. AMER SOC HEMATOLOGY. 2010: 810–11
  • Overdiagnosis of Left Ventricular Noncompaction 14th Annual Scientific Meeting of the Heart-Failure-Society-of-America Singh, G. D., Witteles, R. M. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2010: S107–S107
  • 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 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

  • Left ventricular dysfunction in patients receiving cardiotoxic cancer therapies: Are clinicians responding appropriately? 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Telli, M. L., Yoon, G., Kao, D., Matsuda, K., Witteles, R. M. AMER SOC CLINICAL ONCOLOGY. 2009
  • Left Ventricular Dysfunction in Patients Receiving Cardiotoxic Cancer Therapies: Are Clinicians Responding Appropriately? 58th Annual Scientific Session of the American-College-of-Cardiology Yoon, G., Telli, M., Kao, D., Matsuda, K., Witteles, R. ELSEVIER SCIENCE INC. 2009: A173–A173
  • 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

  • Impedance cardiography is superior to echocardiographic methods for pacing interval optimization Turcott, R. G., Witteles, R. M., Wang, P. J., Vagelos, R. H., Fowler, M. B., Ashley, E. A. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2008: S65
  • Insulin resistance in chronic heart failure - Reply JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Witteles, R. M., Fowler, M. B. 2008; 52 (3): 239-240
  • Independent AV/VV pacing optimization requires operation along mechanical AV delay isochrones Turcott, R. G., Witteles, R., Wang, P. J., Ashley, E. A. ELSEVIER SCIENCE INC. 2008: A21
  • Reversible high-output cardiac failure, an unusual marker of disease status in multiple myeloma LEUKEMIA & LYMPHOMA Kohrt, H., Logan, A., Temmins, C., Witteles, R., Liedtke, M., Medeiros, B. 2008; 49 (3): 581-585

    View details for DOI 10.1080/10428190701861702

    View details for Web of Science ID 000253513300029

    View details for PubMedID 18297538

  • 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
  • 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
  • Reversibility of trastuzumab cardiotoxicity: Is the concept alive and well? Reply JOURNAL OF CLINICAL ONCOLOGY Telli, M. L., Carlson, R. W., Guardino, A. E., Hunt, S. A., Witteles, R. M. 2007; 25 (34): 5533-5534
  • Nesiritide does not cause renal dysfunction in acute decompensated heart failure: A randomized, double-blind, placebo-controlled clinical trial Witteles, R. M., Kao, D., Vagelos, R., Christopherson, D., Matsuda, K., Schreiber, D., Fowler, M. B. ELSEVIER SCIENCE INC. 2007: 63A
  • 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 PubMedID 16360099

  • B-type natriuretic peptide is effective therapy before care ANNALS OF INTERNAL MEDICINE Witteles, R., Matsuda, K., Fowler, M. B. 2004; 141 (11): 895
  • B-type natriuretic peptide is effective therapy before cardiac transplantation Annals of Internal Medicine Witteles R, Matsuda K, Fowler MB 2004; 141 (11): 895
  • 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
  • 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