HeartLine Winter 2008

Beta-Blockade Therapy and Adrenergic Dr. Edmund H. Sonnenblick (1932 - 2007), Receptor Polymorphisms in internationally renowned cardiologist by Ronald Zolty, MD (see page 4)

he emerging fields of pharmacogenetics and pharma- cogenomics involve the search for genetic polymorphisms Tthat influence humoral response to drug therapy. These disciplines offer the promise of A subset, however, appear to have developing individualized, tailored drug functional consequences influencing the therapy on the basis of genotype, thus interplay of genetic and environmental increasing the likelihood of achieving factors on phenotype, including response treatment goals while limiting adverse to medications. effects from drug therapy. Heart failure (HF) represents a major Heterogeneity of clinical response to public health problem because of its high medical therapy, in terms of treatment prevalence, unfavorable outcome, and efficacy, may be explained by multiple economic burden. In HF, activation of variables including: the etiology and the adrenergic system has been shown by severity of the disease being treated, numerous studies to be deleterious to the drug interactions, patient factors such heart in the long term. Several large ran- Also in this Issue: as age, nutritional status, renal and liver domized trials have confirmed the bene- 2 Cardiac Imaging with function, co-morbidities and compli- ficial role of ß-blockade in improving left ance with treatment regimens. Despite ventricular ejection fraction (LVEF) and Radiotracers: SPECT and PET the potential impact of these clinical mortality in HF patients. However, in 3 Cardiac Recovery at Montefiore variables on therapeutic efficacy, it is now spite of the clear benefits of ß-blockade, 4 In Memoriam: recognized that inherited genetic varia- clinical response to ß-blocker therapy Edmund H. Sonnenblick, MD tion in the metabolism and disposition of displays a high degree on inter-individual 5 The Peerless-HF Study drugs, and genetic variation of the targets and inter-ethnic variation. Underlying of drug therapy (such as receptors), play a genetic variation in adrenergic mecha- significant role in individual response to nisms is one potential explanation for Published by the Montefiore-Einstein Heart Center medical therapy. this variability in response. The ß1 and New York, New York 10467 α 2c adrenergic receptors (ARs) play a Co-Directors: Heartline Editors: Data from the Human Genome Project critical role for maintenance of homeo- Richard N. Kitsis, MD Chris Snyder found that small and even modest-sized stasis in the human heart. Certain ß1 Dorros Chair Melissa Crissman nucleotide deletions, insertions, and rear- Professor and Chief Joanne Choi (specifically at amino acid position 49 Division of rangements contribute to diversity within α Correspondence: and 389) and 2c (deletion 322-325) the genome. These variations known as Robert E. Michler, MD AR polymorphisms have been shown to Marketing Department SNPs, or single nucleotide polymor- Belkin Chair 111 East 210th Street act as disease modifiers in HF. Thus, we Professor and Chairman phisms, represent the largest class of New York, NY hypothesized that the different inter- Department of 10467-2490 inter-individual genetic variation. The Cardiothoracic Surgery individual response to ß-blockers might tel. 718 920 7823 majority of these genetic polymorphisms fax 718 405 1938 are likely of little clinical importance. (Continued on back)

1 Cardiac Imaging with Radiotracers: SPECT and PET by Mark Travin, MD

ardiovascular disease, mostly from , is the leading cause of death in the United States, claiming the lives of close to 900,000 people annually, as many as the next Cfour leading causes combined.1 The good news is that over the past decade the death rate from cardiac disease has declined over 20%, in large part the result of improved therapies and greater public attention to cardiac risk factors. Cardiac imaging has also played a crucial role by providing accurate diagnoses of the presence, extent, and severity of coronary disease, thereby helping to better direct patient management. Among cardiac imaging techniques, stress radionuclide myocardial perfusion imaging (MPI) has become a standard for diagnosis, risk stratification, and coronary disease management. Stress MPI can separate low from high risk patients better than clinical data and other cardiac Hybrid PET/CT camera. imaging techniques. As opposed to alternative imaging methods, such as invasive cardiac catheterization and like SPECT, PET can effectively risk stratify patients. An newly developed noninvasive multidetector CT coronary important potential of cardiac PET is that it can quantify angiography that customarily look only at anatomy, MPI coronary blood flow. Development of PET quantitation assesses the functional significance of coronary disease, thus promises great improvement in diagnostic accuracy, often making this technique better at identifying patients at including the ability to identify every patient with high risk of an adverse cardiac event. risk disease, as well as allow detection of patients with New technologies promise to subclinical disease whose response to medical therapies enhance further the clinical can be monitored before a serious problem occurs. utility of MPI. For most of its The variety of imaging molecules that can be developed approximately 30 year history, with PET are numerous. Cardiac PET already has the MPI has used single photon ability to detect metabolically active regions in patients with emission computed tomographic severe congestive heart failure. PET radiotracers that can (SPECT) imaging techniques image the underlying molecular processes of coronary and and tracers, such as thallium-201 other cardiac diseases are under active investigation, thereby or Tc-99m sestamibi. Although making PET a promising tool that should make a dramatic cardiac SPECT MPI has served impact on the #1 cause of death in much of the world. patients well, it is impaired both by technical issues and the limited Dr. Mark I. Travin is the Director of Cardiovascular Nuclear cardiac imaging molecules that Medicine at Montefiore Medical Center and Professor of can be synthesized. A similar Clinical Nuclear Medicine and Clinical Medicine at Albert imaging technique, cardiac Einstein College of Medicine positron emitting tomography 1. Rosamond W, Flegal K, Friday G, Furie K, Go A, Greenlund K, et al. (PET), has for many years been Heart disease and stroke statistics — 2007 update. A report from the American Heart Association Statistics Committee and Stroke Statistics used mostly in research, but Subcommittee. Circulation 2007; 115: e69-e171. in part because of technologic developments, PET has been moving into the clinical mainstream. Recent studies have shown that with visual interpretation techniques, cardiac PET with N13-ammonia or rubidium-82 is more accurate Over the past decade the death rate from than SPECT for diagnosing coronary disease, and that cardiac disease has declined over 20%. 2 Cardiac Recovery at Montefiore

little more than a year after CMS expanded the indications for cardiac rehabilitation more patients are being referred for cardiac rehabilitation from a variety of Aspecialties including internal medicine, family practice, and general practitioners. all aspects of secondary prevention. that, “The evidence is adequate to Dr. Prince has noted a shift in referral conclude that cardiac rehabilitation patterns following the CMS decision. is reasonable and necessary following “Primary care providers today are very acute (AMI), proactive when it comes to preventive coronary artery bypass graft (CABG), medicine and they understand the stable angina pectoris, heart valve importance of exercise. Many of them repair/replacement, percutaneous are active exercisers themselves and transluminal coronary angioplasty they know patients will not initiate (PTCA), and heart or heart- or stick with an exercise program on lung transplant.” The diagnoses their own, especially when there is of PTCA, valve replacement, and fear or anxiety involved. The CMS heart or heart-lung transplant were decision has given increased emphasis new additions to the criteria to to the importance of these programs. meet medical necessity. “With this There is now abundant research that proposed coverage decision, CMS demonstrates the importance and cost seeks to expand coverage to a greater effectiveness of cardiac rehabilitation number of beneficiaries with cardiac programs and primary care providers illness,” said CMS Administrator want to practice evidence based Mark B. McClellan, MD, PhD. “But medicine.” just as importantly, we hope that our proposed decision will raise the The Montefiore-Einstein Heart public’s awareness regarding cardiac Center cardiac rehabilitation facility rehabilitation services in general.” Dr. David Prince, Director of the is located on the East campus close to Cardiac Recovery Program at Jack D. Weiler Hospital. “We accept Dr. David Prince is the Director of the Montefiore-Einstein Heart Center referrals from primary care providers Cardiac Recovery Program at Montefore explained this trend stating, “as as well as cardiologists. In the past Medical Center. For more information awareness of cardiac rehabilitation two years I have also seen more and please go to www.montefiore.org/Heart/ continues to grow the desire of more patients referring themselves Cardiac Rehabilitation. primary care providers to refer after they or their family members 1. Proposed Decision Memo for Cardiac Reha- patients continues to increase. It read about cardiac rehabilitation bilitation Programs. CMS. 12/27/05. makes sense that internists and family online.” Dr. Prince believes that 2. Medicare expanding coverage and services physicians would refer their patients patients today are better informed for cardiac rehab. SeniorJournal.com 1/5/06. to cardiac rehabilitation programs due to accessibility of information http://seniorjournal.com/NEWS/Medicare/ 6-01-05-MedicareExpanding.htm as secondary prevention, since on the internet. “Even if a patient is they are safe and effective. Cardiac not internet savvy, they have kids or rehabilitation is a structured behavior family members who are. We get calls modification program — and every week from family members who behavior modification is at the core want to get their family members of preventive medicine.” enrolled.” Although in the past many primary Following a two year review care providers depended on their process, the Centers for Medicare colleagues in cardiology to manage and Medicaid Services concluded

3 In Memoriam Edmund H. Sonnenblick, MD December 7, 1932 - September 22, 2007 by Richard N. Kitsis, MD

he Montefiore-Einstein Heart Center and the world lost a giant in the field of cardiac care during the fall of 2007. Dr. Edmund H. Sonnenblick, a cardiologist whose research Tformed a basis for the modern treatment of heart failure, which has extended the lives of millions of people, died at the age of 74 at his home in Connecticut.

The following is a composite of remarks mechanical underpinnings of cardiac novel biological insights. It is rare, that Dr. Richard N. Kitsis, co-director of function. The resulting concepts of however, that a single scientist is the Montefiore-Einstein Heart Center, preload, afterload, and contractility able to both make the fundamental delivered upon the posthumous bestowing are used on a daily basis by physicians discovery and translate it into clinical of the American Heart Association’s throughout the world. practice to save lives. Dr. Sonnenblick Research Achievement Award to Dr. was able to do this, and this is an As impressive as all of this is, he Sonnenblick, and from a memorial important part of his legacy. then proceeded to use the electron service that took place in New York microscope, a new tool at the time, to During his career, Dr. Sonnenblick earlier in October of 2007. go one step further. He determined trained more than 300 individuals in Dr. Sonnenblick was different how the alignment of contractile clinical cardiology and cardiovascular things to each of us: loving husband; proteins in heart muscle cells explains research. He was an exceptionally devoted father, father-in-law, and some of the mechanical principles patient and supportive mentor. In grandfather; caring physician; that he had discovered. the mid-1980s, basic cardiovascular towering scientist; nurturing teacher research underwent a fundamental Dr. Sonnenblick then applied these and mentor; kind human being; loyal shift from investigations that were basic concepts to human disease. friend; and gentleman. primarily physiological in nature to His ideas contributed heavily to ones that melded physiology with Dr. Sonnenblick was truly a giant the development by others of ACE molecular biology and genetics. in the field of cardiology. One of inhibitors as a treatment for heart Although a physiologist, Dr. the most important cardiovascular failure. Moreover, Dr. Sonnenblick’s Sonnenblick showed exceptional physiologists of the 20th century. understanding of cardiac physiology vision and foresight when, in A legend and icon. In 1961, when was so deep that it often gave collaboration with Drs. Leslie he was only 29 years old, he carried him the courage to go against Leinwand and James Scheuer at out fundamental scientific studies prevailing dogma. For example, Albert Einstein, he helped to create that revealed for the first time the based on physiology, he theorized what was perhaps the world’s first mechanical principles that govern that ß-blockers, which were then training program in molecular cardiac function. This research was contraindicated in heart failure, cardiology. The graduates of this performed at the National Heart might actually be beneficial in this program include multiple outstanding Institute — now known as the syndrome. This proved correct. As scientists and leaders in cardiology National Heart, Lung, and Blood we all know, the combination of and cardiovascular research. Institute — of the National Institutes ACE inhibitors and ß-blockers has of Health. Working first with Dr. extended the lives of countless heart Dr. Richard N. Kitsis is co-director of Stanley Sarnoff and later with Drs. failure patients. the Montefiore-Einstein Heart Center. Eugene Braunwald and John Ross, The most ground-breaking advances Jr., Dr. Sonnenblick delineated the in clinical medicine often begin with

4 The Peerless-HF Study; A Novel Treatment for Advanced Heart Failure by Simon Maybaum, MD

eart failure is a condition that affects more than 5 million people in the United States, with 550,000 new diagnoses each year.

PEERLESS-HF / Paracor Medical H • HeartNet™ device: ventricular support to reduce wall stress • Primary endpoints: peak vO2 and 6-min walk at 6 months; quality of life questionnaire • Major inclusion criteria: – Symptomatic heart failure ACC/AHA stage C – LVEF < 35% – LVEDD < 85 mm, LVEDDi < 40 mm/m2 – Peak vO2 10.0-20.0 mL/min/kg – Heart failure duration > 6 months http://www.paracor.com

As the disease progresses the heart may surgical operation than open heart We continue to evaluate patients become enlarged and weak so that it surgery. By reducing wall stress, the who express interest in the trial and/ can no longer pump blood efficiently implant may help deter or reverse the or may benefit from this procedure. to the rest of the body, affecting heart enlargement process present in Please support us by considering this the ability to perform even simple heart failure patients. clinical trial for your advanced heart activities. Heart failure medications can failure patients who are not responding The PEERLESS-HF study is significantly improve symptoms and to conventional therapy. For more conducted in New York exclusively prolong life, however, some patients information about our center and the at the Montefiore-Einstein Heart become refractory to these therapies. PEERLESS-HF study, please contact Center’s Center for Advanced Cardiac Some may eventually be required Audrey Kleet, NP at 718-920-2626. Therapy by Dr. Simon Maybaum to receive a heart transplant. As a and Dr. David D’ Alessandro. Our Dr. Maybaum is co-director of the result, new drug and device studies first patient enrolled, underwent the Center for Advanced Cardiac Therapy are continuously designed to help HeartNet™ implant in late October at Montefiore-Einstein Heart Center. this patient population, and exploring 2007 and has done extremely well. promising approaches to treating heart failure continues to be a priority at the Center for Advanced Cardiac Therapy at Montefiore-Einstein Heart Center. Our center is currently participating in a novel study for heart failure patients. The PEERLESS-HF trial, sponsored by Paracor Medical, is a multi-center device study to test the safety and efficacy of the HeartNet™ Ventricular A day of insight and innovation with international Support System compared to standard experts and keynote speaker Bernadine Healy, MD heart failure therapy. This innovative technology consists of an elastic nitinol mesh implant that is wrapped around the patient’s heart to provide physical support for the walls of the heart; it is implanted via a deployment system that requires a much less invasive

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Beta-Blockade Therapy (continued from cover) Admitting And be due to genetic polymorphisms of the 3) The combination of the ß1 α Transfers ß1 and 2c AR genes. Arginine389 homozygous and α 600 patients with LVEF≤40% from 2cDeletion322-325 demonstrated Made Easy. any etiology were selected from the HF a significant change in LVEF on ß- Clinic at the University of Colorado blockers compared to ß1 Glycine389 α Hospital and correlation between the carrier and 2cwild-type. α different ß1 and 2c-AR polymorphisms In summary, in HF these different ß1 α and LVEF response to ß-blockade and 2c AR polymorphisms were shown therapy was evaluated. to be important predictor of LVEF We demonstrated in this retrospective improvement with ß-blockers. study: Currently at The Montefiore-Einstein 1) A significant association between ß1 Heart Center we are conducting similar AR genotype and the magnitude of studies, mainly in the African American improvement in LVEF in patients and Hispanic HF populations, to deter- with HF when treated with ß-block- mine if the results obtained in Colorado ers. In other words, ß1 AR polymor- are reproducible in other ethnicities. 1-888-ME-HEART phisms are predictive of improvement In conclusion, pharmacogenomics has • One call is all you make in LVEF in patients who otherwise the potential to revolutionize the field of present with similar clinical features, heart failure therapy. The preceding ex- • 24/7 service including LVEF and similar ß-blocker amples of genetic polymorphism relevant usage. Specifically subjects that were to the treatment of heart failure with be- • Admit or transfer your own Arginine389 homozygous and/or ta-blockers illustrate the promise of this patients Glycine49 had a greater LVEF im- exciting area. The study mentioned in • Track arrival of patients provement compared with Glycine389 this article provides a scientific basis for carriers and/or Serine49 carriers. the use of genomic information for the • Track progress of patients 2) A strong correlation between the individualization of heart failure therapy For more information call based in a patient’s genetic profile. different ß1-AR haplotypes (based on 1-888-ME-HEART codon 49 and 389 polymorphisms) (1-888-634-3278) or visit and the difference in the LVEF For more information, please contact www.montefiore.org/heart improvement when treated with Dr. Zolty’s office at 718-430-3544. ß-blockers.

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