Feeds:
Posts
Comments

Posts Tagged ‘Aviva Lev-Ari’


PCCI’s 7th Annual Roundtable “Crowdfunding for Life Sciences: A Bridge Over Troubled Waters?”

Reporter: Stephen J. Williams, Ph.D.

 

http://www.rxpcci.com/meetings.htm

Monday, May 12 2014 Embassy Suites Hotel, Chesterbrook PA 6:00 -9:30 PM

Pharmaceutical Consulting Consortium International Inc. presents their 7th annual Roundtable on Crowdfunding for the Life Sciences and how this funding mechanism applies to early stage life science companies and changes the funding landscape. The conference will examine the types of crowdfunding out there and attempts to answer many questions including:

  • Which one is right for which new companies at which stage of the funding process?
  • And how will choosing the right or wrong one influence follow-on funders and funding rounds?
  • Will the advent of crowdfunding speed up the investment process?
  • Will it really bridge the yawning “valley of death”?

The panel is made up of notables and practitioners who will be called upon to deal with the pros and cons of crowdfunding in real life and let them discuss how all this is likely to apply to life science entrepreneurs and investors.

The panel includes:

  1. Mark Roderick, Attorney Flaster/Greenberg PC (Moderator)
  2. Valerie Gaydos, President, Capital Growth (represents angel/venture community)
  3. Samuel Wertheimer, Chief Investment Officer, Poliwogg Darrick Mix
  4. Duane Morris, LLP (journalist who covers crowdfunding

Register by clicking on www.rxpcci.com and following directions The event will be webcast.

Leaders in Pharmaceutical Business Intelligence had recently launched a new, real-time based methodology for meeting coverage using social media as a platform to foster discussion and commentary.

This methodology is described in the following post REAL TIME Cancer Conference Coverage: A Novel Methodology for Authentic Reporting on Presentations and Discussions launched via Twitter.com @ The 2nd ANNUAL Sachs Cancer Bio Partnering & Investment Forum in Drug Development, 19th March 2014 • New York Academy of Sciences • USA

This new method was successfully used and curated at the 2nd Annual Sachs Cancer Bio Partnering &Investment Forum at the New York Academy of Sciences and will be featured at the forthcoming Sachs Global Conferences in 2014 and 2015.

Related articles on this site include:

conceived: NEW Definition for Co-Curation in Medical Research

Cancer Biology and Genomics for Disease Diagnosis, Volume One Pre-ePub Announcement

Volatile Organic Compounds (VOCs) as Biomarkers in Cancer Detection: • Alnion Ranked #1 in “Top 10 Israeli medical advances to watch in 2014”.

Investing and inventing: Is the Tango of Mars and Venus Still on

SACHS Associates, London – Planning Forthcoming Conferences: 2014 – 2015

 

 

 

Read Full Post »


Heroes in Medical Research: Developing Models for Cancer Research

 

Author, Curator: Stephen J. Williams, Ph.D.

The current rapid progress in cancer research would have never come about if not for the dedication of past researchers who had developed many of the scientific tools we use today. In this issue of Heroes in Medical Research I would like to give tribute to the researchers who had developed the some of the in-vivo and in-vitro models which are critical for cancer research.

 

The Animal Modelers in Cancer Research

Helen Dean King, Ph.D. (1869-1955)

Helen Dean King

Helen Dean King, Ph.D. from www.ExplorePAhistory.com; photo Courtesy of the Wistar Institute Archive Collection, Philadelphia, PA

 

 

The work of Dr. Helen Dean King on rat inbreeding led to development of strains of laboratory animals. Dr. King taught at Bryn Mawr College, then worked at University of Pennsylvania and the Wistar Institute under famed geneticist Thomas Hunt Morgan, researching if inbreeding would produce harmful genetic traits.   At University of Pennsylvania she examined environmental and genetic factors on gender determination.

 

 

 

 

Important papers include [1-6]as well as the following contributions:

“Studies in Inbreeding”, “Life Processes in Gray Norway Rats During Fourteen Years in Captivity”, doctoral thesis on embryologic development in toads (1899)

 

Milestones include:

 

1909    started albino rat breeding and bred 20 female and male from same litter (King colony) to 25

successive generations (inbreeding did not cause harmful traits)

 

1919     started to domesticate the wild Norwegian rats that ran thru Philadelphia (six pairs Norway rats

thru 28 generations)

A good reference for definitions of rat inbreeding versus line generation including a history of Dr. King’s work can be found at the site: Munificent Mischief Rattery and a brief history here.[7] In addition, Dr. King had investigated using rat strains as a possible recipient for tumor cells. The work was an important advent to the use of immunodeficient models for cancer research.

 

As shown below Philadelphia became a hotbed for research into embryology, development, genetics, and animal model development.

 

Beatrice Mintz, Ph.D.

(Beatrice Minz, Ph.D.; photo credit Fox Chase Cancer Center, www.pubweb.fccc.edu) Mintz

Dr. Mintz, an embryologist and cancer researcher from Fox Chase Cancer Center in Philadelphia, PA, contributed some of the most seminal discoveries leading to our current understanding of genetics, embryo development, cellular differentiation, and oncogenesis, especially melanoma, while pioneering techniques which allowed the development of genetically modified mice.

If you get the privilege of hearing her talk, take advantage of it. Dr. Mintz is one of those brilliant scientists who have the ability to look at a clinical problem from the viewpoint of a basic biological question and, at the same time, has the ability to approach the well-thought out questions with equally well thought out experimental design. For example, Dr. Mintz asked if a cell’s developmental fate was affected by location in the embryo. This led to her work by showing teratocarcinoma tumor cells in the developing embryo could revert to a more normal phenotype, essentially proving two important concepts in development and tumor biology:

  1. The existence of pluripotent stem cells
  2. That tumor cells are affected by their environment (which led to future concepts of the importance of tumor microenvironment on tumor growth

Other seminal discoveries included:

  • Development of the first mouse chimeras using novel cell fusion techniques
  • With Rudolf Jaenisch in 1974, showed integration of viral DNA from SV40, could be integrated into the DNA of developing mice and persist into adulthood somatic cells, the first transgenesis in mice which led ultimately to:
  • Development of the first genetically modified mouse model of human melanoma in 1993

Her current work, seen on the faculty webpage here, is developing mice with predisposition to melanoma to uncover risk factors associated with the early development of melanoma.

In keeping with the Philadelphia tradition another major mouse model which became seminal to cancer drug discovery was co-developed in the same city, same institute and described in the next section.

It is interesting to note that the first cloning of an animal, a frog, had taken place at the Institute for Cancer Research, later becoming Fox Chase Cancer Center, which was performed by Drs. Robert Briggs and Thomas J. King and reported in the 152 PNAS paper Transplantation of Living Nuclei From Blastula Cells into Enucleated Frogs’ Eggs.[8]

 

 The Immunodeficient Animal as a Model System for Cancer Research – Dr. Mel Bosma, Ph.D.

 

Bosma

Melvin J. Bosma, Ph.D.; photo credit Fox Chase Cancer Center

In the summer of 1980 at Fox Chase Cancer Center, Dr. Melvin J. Bosma and his co-researcher wife Gayle discovered mice with deficiencies in common circulating antibodies and since, these mice were littermates, realized they had found a genetic defect which rendered the mice immunodeficient (upon further investigation these mice were unable to produce mature B and T cells). These mice were the first scid (severe combined immunodeficiency) colony. The scid phenotype was later found to be a result of a spontaneous mutation in the enzyme Prkdc {protein kinase, DNA activated, catalytic polypeptide} involved in DNA repair, and ultimately led to a defect in V(D)J recombination of immunoglobulins.

The emergence of this scid mouse was not only crucial for AIDS research but was another turning point in cancer research , as researchers now had a robust in-vivo recipient for human tumor cells. The orthotopic xenograft of human tumor cells now allowed for studies on genetic and microenvironmental factors affecting tumorigenicity, as well as providing a model for chemotherapeutic drug development (see Suggitt for review and references)[9]. A discussion of the pros and cons of the xenograft system for cancer drug discovery would be too voluminous for this post and would warrant a full review by itself. But before the advent of such scid mouse systems researchers relied on spontaneous and syngeneic mouse tumor models such as the B16 mouse melanoma and Lewis lung tumor model.

Other scid systems have been developed such as in the dog, horse, and pig. Please see the following post on this site The SCID Pig: How Pigs are becoming a Great Alternate Model for Cancer Research. The athymic (nude) mouse (nu/nu) also is a popular immunodeficient mouse model used for cancer research

Two other in-vivo tumor models: Patient Derived Xenografts (PDX) and Genetically Engineered Mouse models (GEM) deserve their own separate discussion however the success of these new models can be attributed to the hard work of the aforementioned investigators. Therefore I will post separately and curate PDX and GEM models of cancer and highlight some new models which are having great impact on cancer drug development.

 

References

1.         Loeb L, King HD: Transplantation and Individuality Differential in Strains of Inbred Rats. The American journal of pathology 1927, 3(2):143-167.

2.         Lewis MR, Aptekman PM, King HD: Retarding action of adrenal gland on growth of sarcoma grafts in rats. J Immunol 1949, 61(4):315-319.

3.         Aptekman PM, Lewis MR, King HD: Tumor-immunity induced in rats by subcutaneous injection of tumor extract. J Immunol 1949, 63(4):435-440.

4.         Lewis MR, Aptekman PM, King HD: Inactivation of malignant tissue in tumor-immune rats. J Immunol 1949, 61(4):321-326.

5.         Lewis MR, King HD, et al.: Further studies on oncolysis and tumor immunity in rats. J Immunol 1948, 60(4):517-528.

6.         Aptekman PM, Lewis MR, King HD: A method of producing in inbred albino rats a high percentage of immunity from tumors native in their strain. J Immunol 1946, 52:77-86.

7.         Ogilvie MB: Inbreeding, eugenics, and Helen Dean King (1869-1955). Journal of the history of biology 2007, 40(3):467-507.

8.         Briggs R, King TJ: Transplantation of Living Nuclei From Blastula Cells into Enucleated Frogs’ Eggs. Proceedings of the National Academy of Sciences of the United States of America 1952, 38(5):455-463.

9.         Suggitt M, Bibby MC: 50 years of preclinical anticancer drug screening: empirical to target-driven approaches. Clinical cancer research : an official journal of the American Association for Cancer Research 2005, 11(3):971-981.

 

Other posts on this site about Cancer, Animal Models of Disease, and other articles in this series include:

The SCID Pig: How Pigs are becoming a Great Alternate Model for Cancer Research

A Synthesis of the Beauty and Complexity of How We View Cancer

Guidelines for the welfare and use of animals in cancer research

Importance of Funding Replication Studies: NIH on Credibility of Basic Biomedical Studies

FDA Guidelines For Developmental and Reproductive Toxicology (DART) Studies for Small Molecules

Report on the Fall Mid-Atlantic Society of Toxicology Meeting “Reproductive Toxicology of Biologics: Challenges and Considerations:

What`s new in pancreatic cancer research and treatment?

Heroes in Medical Research: Dr. Carmine Paul Bianchi Pharmacologist, Leader, and Mentor

Heroes in Medical Research: Dr. Robert Ting, Ph.D. and Retrovirus in AIDS and Cancer

Heroes in Medical Research: Barnett Rosenberg and the Discovery of Cisplatin

Richard Lifton, MD, PhD of Yale University and Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension

Reuben Shaw, Ph.D., a geneticist and researcher at the Salk Institute: Metabolism Influences Cancer

 

Read Full Post »


Leaders in Pharmaceutical Business Intelligence announce their latest addition to the BioMed e-Series ebooks: Cancer Biology and Genomics for Disease Diagnosis, Volume One.

This ebook is a compendium of recent breakthroughs, articles, and commentary on cancer research, cancer detection and diagnosis and treatment, written and curated by a team of PhD, MD, MD/PhD, PharmD clinicians, scientists, and writers having expertise in oncology.

Leaders in Pharmaceutical Business Intelligence will demonstrate this e-book at  The Sachs Cancer Bio Partnering and Investment Forum, held March 19, 2014 at the New York Academy of Sciences in New York, USA.

A post on this site entitled The 2nd ANNUAL Sachs Cancer Bio Partnering & Investment Forum Promoting Public & Private Sector Collaboration & Investment in Drug Development, 19th March 2014 • New York Academy of Sciences • USA explains the program, agenda, a description of this investment conference.

A flyer of the demonstration by Leaders in Pharmaceutical Intelligence is included below (please click on picture):

SACHS FLYER 2014 CANCER EBOOKjpeg-page1

SACHS FLYER 2014 CANCER EBOOKjpeg-page2

 

The flyer can be downloaded as a .pdf here: SACHS FLYER 2014 CANCER EBOOK

April 2014 will see LAUNCH of next VOLUME in Series C: e-Books on Cancer & Oncology Radiation Oncology & Immunotherapy in Cancer

Read Full Post »


Juno’s approach eradicated cancer cells in 10 of 12 leukemia patients, indicating potential to transform the standard of care in oncology

Reporter: Aviva Lev-Ari, PhD, RN

Immunotherapy startup lands $120M Series A for cancer-killing drugs

December 4, 2013 | By 

Once-rival researchers from the Fred Hutchinson Cancer Research Center and Memorial Sloan-Kettering Cancer Center have decided to join forces and dive into drug development, hauling in a massive $120 million Series A round to advance “smart” T cells that spur an immunologic attack on cancers.

Their startup, Juno Therapeutics, unites some of the brightest minds in immunotherapy development around the idea of using chimeric antigen receptors to reprogram a patient’s T cells and transform them into cancer-fighting agents. Juno’s leadership believes the platform will lead to promising drug candidates for hematologic and solid tumor cancers, and they’ve recruited the Seattle Children’s Research Institute to pitch in on pediatric development.

The $120 million raise, provided by investors like ARCH Venture Partners and the Alaska Permanent Fund, will help get some of Juno’s candidates through Phase I, and the company is already trumpeting its early results as “unprecedented.” Juno’s drug completely eradicated cancer cells in 10 of 12 leukemia patients after a single infusion, the company said–results cofounder and former National Cancer Institute Director Richard Klausner called the most exciting data he’s seen in 30 years of immunotherapy research. 

The new company has yet to disclose side effects, survival rates or full-scale data from those studies, but the early promise was enough to lure some high-dollar backing, and Juno has recruited a CEO with experience bringing a T cell-altering immunotherapy to market, installing former Dendreon chief Hans Bishop to lead the way. And the company is hardly short on ambition, setting course on a broad clinical program with plans to run concurrent trials on numerous cancers, Bishop said.

“Juno brings together renowned scientists and exceptional investment partners to launch and quickly scale an enterprise that will deliver cutting-edge cancer immunotherapy,” Bishop said in a statement. “It is a completely unique opportunity that holds the potential to truly save lives while transforming how we treat cancer.”

- read the announcement
- check out FiercePharmaManufacturing‘s take

Related Articles:
Merck spotlights promising data on ‘breakthrough’ cancer immunotherapy MK-3475
Roche, immatics forge immunotherapy cancer R&D deal worth up to $1B
Immune Design recruits new team, lands $32.5M for cancer immunotherapies

Read more: Immunotherapy startup lands $120M Series A for cancer-killing drugs – FierceBiotech http://www.fiercebiotech.com/story/immunotherapy-startup-lands-120m-series-cancer-killing-drugs/2013-12-04#ixzz2qPjUNOxe

SOURCE

Amazon ($AMZN) founder and new media mogul Jeff Bezos is investing a bit of his personal fortune in Seattle-based Juno Therapeutics, a biotech startup that’s been making some big waves in the immunotherapy world.

Just weeks after Juno launched with great fanfare, the biotech announced that Bezos’ personal investment group, Bezos Expeditions, helped add $25 million to Juno’s already bountiful $120 million A round with the assistance of Venrock. Juno also added some marquee players to its board today, including Marc Tessier-Lavigne, the former CSO at Genentech and current president of The Rockefeller University in New York City.

Juno is the brainchild of some of the world’s top scientists at the Fred Hutchinson Cancer Research Center, Memorial Sloan-Kettering and the Seattle Children’s Research Institute. The company in-licensed technology from St. Jude’s regarding chimeric antigen receptors, which its founders believe can be used to reprogram immune T cells that can then be directed against cancer cells. That CAR-T tech is similar to the approach being used by Novartis ($NVS) and the University of Pennsylvania’s Carl June, and the principals are already deep into litigation over the intellectual property that’s being employed.

In early research, the founders say that Juno’s approach eradicated cancer cells in 10 of 12 leukemia patients, indicating potential to transform the standard of care in oncology.

Bezos has been investing some of his Amazon fortune in a variety of ventures, including Business Insider, the Washington Post and Sapphire Energy. But this is the first straight biotech investment that Fierce has come across so far.

“This is an exciting time for Juno,” said Hans Bishop, CEO, in a statement. “The investments from Bezos Expeditions and Venrock will help accelerate our growth as we work to transform how we treat cancer.”

SOURCE
From: FierceBiotech <editors@fiercebiotech.com>
Date: Tue, 14 Jan 2014 18:24:32 +0000 (GMT)
To: <avivalev-ari@alum.berkeley.edu>

Read Full Post »


Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))

Reviewer and Co-Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

The role of ion channels in Na(+)-K(+)-ATPase: regulation of ion
transport across the plasma membrane has been studied by our Team in 2012 and 2013. This is article TWELVE in a 13 article series listed at the end of this article.

Chiefly, our sources of inspiration were the following:

1.            2013 Nobel work on vesicles and calcium flux at the neuromuscular junction

Machinery Regulating Vesicle Traffic, A Major Transport System in our Cells 

The 2013 Nobel Prize in Physiology or Medicine is awarded to Dr. James E. Rothman, Dr. Randy W. Schekman and Dr. Thomas C. Südhof for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells. This represents a paradigm shift in our understanding of how the eukaryotic cell, with its complex internal compartmentalization, organizes the routing of molecules packaged in vesicles to various intracellular destinations, as well as to the outside of the cell. Specificity in the delivery of molecular cargo is essential for cell function and survival. 

http://www.nobelprize.org/nobel_prizes/medicine/laureates/2013/advanced-medicineprize2013.pdf

Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/10/synaptotagmin-functions-as-a-calcium-sensor-how-calcium-ions-regulate-the-fusion-of-vesicles-with-cell-membranes-during-neurotransmission/

2. Perspectives on Nitric Oxide in Disease Mechanisms

available on Kindle Store @ Amazon.com

http://www.amazon.com/dp/B00DINFFYC

http://pharmaceuticalintelligence.com/biomed-e-books/series-a-e-books-on-cardiovascular-diseases/perspectives-on-nitric-oxide-in-disease-mechanisms-v2/

3.            Professor David Lichtstein, Hebrew University of Jerusalem, Dean, School of Medicine

Lichtstein’s main research focus is the regulation of ion transport across the plasma membrane of eukaryotic cells. His work led to the discovery that specific steroids that have crucial roles, as the regulation of cell viability, heart contractility, blood pressure and brain function. His research has implications for the fundamental understanding of body functions, as well as for several pathological states such as heart failure, hypertension and neurological and psychiatric diseases.

Physiologist, Professor Lichtstein, Chair in Heart Studies at The Hebrew University elected Dean of the Faculty of Medicine at The Hebrew University of Jerusalem

Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/18/physiologist-professor-lichtstein-chair-in-heart-studies-at-the-hebrew-university-elected-dean-of-the-faculty-of-medicine-at-the-hebrew-university-of-jerusalem/

4.            Professor Roger J. Hajjar, MD at Mount Sinai School of Medicine

Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/

5.            Seminal Curations by Dr. Aviva Lev-Ari on Genetics and Genomics of Cardiovascular Diseases with a focus on Conduction and Cardiac Contractility

Aviva Lev-Ari, PhD, RN

Aviva Lev-Ari, PhD, RN

Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Other related research by the Team of Leaders in Pharmaceutical Business Intelligence published on the Open Access Online Scientific Journal

http://pharmaceuticalintelligence.com

See References to articles at the end of this article on

  • ION CHANNEL and Cardiovascular Diseases

http://pharmaceuticalintelligence.com/?s=Ion+Channel

  • Calcium Role in Cardiovascular Diseases – The Role of Calcium Calmodulin Kinase  (CKCaII) and Ca(2) flux
  • Mitochondria and Oxidative Stress Role in Cardiovascular Diseases

Thus, the following article follows a series of articles on ion-channels and cardiac contractility mentioned, above. The following article is closely related to the work of Prof. Lichtstein.

These investigators studied the possible correlation between

  • Myocardial Ischemia (Coronary Artery Disease (CAD)) aka Ischemic Heart Disease (IHD) and
  • single-nucleotide polymorphisms  (SNPs) genes encoding several regulators involved in Coronary Blood Flow Regulation (CBFR), including
  • ion channels acting in vascular smooth muscle and/or
  • endothelial cells of coronary arteries.

They completely analyzed exon 3 of both KCNJ8 and KCNJ11 genes (Kir6.1 and Kir6.2 subunit, respectively) as well as

  • the whole coding region of KCN5A gene (Kv1.5 channel).
The work suggests certain genetic polymorphisms may represent a non-modifiable protective factor that could be used
  • to identify individuals at relatively low-risk for cardiovascular disease
  • an independent protective role of the
    • rs5215_GG against developing CAD and
    • a trend for rs5219_AA to be associated with protection against coronary microvascular dysfunction

Their findings are a lead into further investigations on ion channels and IHD affecting the microvasculature.

Role of genetic polymorphisms of ion channels in the pathophysiology of coronary microvascular dysfunction and ischemic heart disease

BasicResCardiol(2013)108:387   http//dx.dio.org/10.1007/s00395-013-0387-4

F Fedele1•M Mancone1•WM Chilian2•P Severino2•E Canali•S Logan•ML DeMarchis3•M Volterrani4•R Palmirotta3•F Guadagni3

1Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences,Sapienza University of Rome, UmbertoI Policlinic, Rome, Italy  e-mail:francesco.fedele@uniroma1.it
2Department of Integrative Medical Sciences, Northeastern Ohio Universities College of Medicine, Rootstown,OH
3Department of Advanced Biotechnologies and Bioimaging, IRCCS San Raffaele Pisana,Rome,It
4Cardiovascular Research Unit, Department of Medical Sciences, Centre for Clinical and Basic Research, Raffaele Pisana, Rome, Italy (CBFR)

BasicResCardiol(2013)108:387   http//dx.dio.org/10.1007/s00395-013-0387-4
This article is published with open access at Springerlink.com

Abstract

Conventionally,ischemic heart disease (IHD) study is equated with large vessel coronary disease (CAD). However, recent evidence has suggested

  • a role of compromised microvascular regulation in the etiology of IHD.

Because regulation of coronary blood flow likely involves

  • activity of specific ion-channels, and
  • key factors involved in endothelium-dependent dilation,

genetic anomalies of ion-channels or specific endothelial-regulators may underlie coronary microvascular disease.

We aimed to evaluate the clinical impact of single-nucleotide polymorphisms in genes encoding for

  • ion-channels expressed in the coronary vasculature and the possible
  • correlation with IHD resulting from microvascular dysfunction.

242 consecutive patients who were candidates for coronary angiography were enrolled. A prospective, observational, single-center study was conducted, 

  • analyzing genetic polymorphisms relative to

(1) NOS3 encoding for endothelial nitric oxide synthase (eNOS);
(2) ATP2A2 encoding for the Ca/H-ATP-ase pump (SERCA);
(3) SCN5A encoding for the voltage-dependent Na channel (Nav1.5);
(4) KCNJ8 and in KCNJ11 encoding for the Kir6.1and Kir6.2 subunits
of genetic K-ATP channels, respectively;and
(5) KCN5A encoding for the voltage-gated K channel (Kv1.5).

No significant associations between clinical IHD manifestations and

  • polymorphisms for SERCA, Kir6.1, and Kv1.5. were observed (p[0.05),

whereas specific polymorphisms detected in eNOS, as well as in Kir6.2 and Nav1.5 were found to be correlated with

  • IHD and microvascular dysfunction.

 Interestingly, genetic polymorphisms of ion-channels  seem to have an important clinical impact

  • influencing the susceptibility for microvascular dysfunction and (IHD,
  • independent of the presence of classic cardiovascular risk factors: atherosclerosis   

http//dx.dio.org/10.1007/s00395-013-0387-4

Keywords: Ion-channels, Genetic polymorphisms, Coronary microcirculation, Endothelium, Atherosclerosis Ischemic heart disease

 Introduction

Historically, in the interrogation of altered vascular function in patientswith ischemic heart disease (IHD), scientists have focused their attention on the correlation between

  • endothelial dysfunction and
  • atherosclerosis [11, 53, 6567].

The endothelium-independent dysfunction in coronary microcirculation and its possible correlations with  

  • atherosclerotic disease and
  • myocardial ischemia has not been extensively investigated.

In normal conditions, coronary blood flow regulation (CBFR) is mediated by several different systems, including

  • endothelial,
  • nervous,
  • neurohumoral,
  • myogenic, and
  • metabolic mechanisms [2, 10, 14, 15, 63, 64, 69].

Physiologic CBFR depends also on several ion channels, such as

  • ATP-sensitive potassium (KATP) channels,
  • voltage-gated potassium (Kv) channels,
  • voltage-gated sodium (Nav) channels, and others.

Ion channels regulate the concentration of calcium in both

  • coronary smooth muscle and endothelial cells, which
  • modulates the degree of contractile tone in vascular muscle and
  • the amount of nitric oxide that is produced by the endothelium

Ion channels play a primary role in the rapid response of both

  • the endothelium and vascular smooth muscle cells of coronary arterioles
  • to the perpetually fluctuating demands of the myocardium for blood flow
    [5, 6, 13, 18, 33, 45, 46, 51, 52, 61, 73, 75].

Despite this knowledge, there still exists an important gap about 

  • the clinical relevance and 
  • causes of microvascular dysfunction in IHD

By altering the overall

  • regulation of blood flow in the coronary system,
  • microvascular dysfunction could alter the normal distribution of shear forces in large coronary arteries

Proximal coronary artery stenosis could

  • contribute to microvascular dysfunction [29, 60]. But
  • ion channels play a critical role in microvascular endothelial
  • and smooth muscle function.

Therefore, we hypothesized  that alterations of coronary ion  channels could be the primary cause in a chain of events leading to

  • microvascular dysfunction and 
  • myocardial ischemia

independent of the presence of atherosclerosis.

Therefore, the objective of our study was to evaluate the possible correlation between

  • IHD and single-nucleotide polymorphisms  (SNPs) for genes encoding several regulators involved in CBFR, including
  • ion channels acting in vascular smooth muscle and/or
  • endothelial cells of coronary arteries.

Discussion

Implications of the present work. This study describes the possible correlation of polymorphisms in genes encoding for CBFR effectors (i.e., ion channels, nitric oxide synthase, and SERCA) with the susceptibility for microcirculation dysfunction and IHD.

Our main findings are as follows: (Group 3 – Normal Patients – anatomically and functionally normal coronary arteries).

  • In Group 3, the genotype distribution of SNP rs5215 (Kir6.2/KCNJ11) moderately deviates from the HW equilibrium (p = 0.05).
  • In Group 1 (CAD), the polymorphism rs6599230 of Nav1.5/SCN5A showed deviation from HW equilibrium (p = 0.017).
  • The genotypic distribution of rs1799983 polymorphism for eNOS/NOS3 is inconsistent with the HW equilibrium in groups 1, 2, and 3 (p = 0.0001, p = 0.0012 and p = 0.0001, respectively).

Haplotype analyses revealed that there is no linkage disequilibrium between polymorphisms of the analyzed genes. There was no significant difference in the prevalence of T2DM (p = 0.185) or dyslipidemia (p = 0.271) between groups, as shown in Table2. In regards to genetic characteristics, no significant differences between the three.

1. A marked HW disequilibrium in the genotypic distribution of rs1799983 polymorphism for eNOS/NOS3 was observed in all three populations. Moreover, this SNP seems to be an independent risk factor for microvascular dysfunction, as evidenced by multivariate analysis;
2. The SNPs rs5215_GG, rs5218_CT, and rs5219_AA for Kir6.2/KCJ11 could reduce susceptibility to IHD, since they were present more frequently in patients with anatomically and functionally normal coronary arteries;
3. In particular, with regard to rs5215 for Kir6.2/KCJ11, we observed a moderate deviation from the HW equilibrium in the genotypic
distribution in the control group. In addition, this genotype appears to be an independent protective factor in the development of IHD, as evidenced by multivariate analysis;
4. Furthermore, the trend observed for the SNP  rs5219_AA of Kir6.2/KCNJ11 may suggest an independent protective factor  in the development of coronary microvascular dysfunction
5. The rs1805124_GG genotype of Nav1.5/SCN5A seems to play a role against CAD;
6. No association seems to exist between the polymorphisms of SERCA/ATP2A2, Kir6.1/KCNJ8, and Kv1.5/KCNA5 and the presence of IHD;
7. All groups are comparable regarding the cardiovascular risk factors of T2DM and dyslipidemia, illustrating a potentially important implication of genetic polymorphisms in the susceptibility to IHD.

It is important to underline that the control group (Group 3) is a high-risk population, because of their cardiovascular risk factors

  • hypertension = 17 %,
  • T2DM = 34.1 %,
  • dyslipidemia = 41.4 %,

with an appropriate indication for coronary angiography, in accordance with current guidelines. Nevertheless, these patients were demonstrated to have both anatomically and functionally normal coronary arteries. Moreover, as shown in Tables 2 and 3, we observed that

  • rs5215_GG, rs5218_CT and rs5219_AA for Kir6.2/KCNJ11 had a higher prevalence in this group,compared to patients with CAD
  • and patients with microvascular dysfunction.

Moreover, as shown in Table 4, the presence of the rs5215_GG polymorphism for the Kir6.2 subunit was

  • inversely correlated with the prevalence of cardiovascular risk factors and CAD,whereas
  • rs5219_AA of the Kir6.2 subunit trended towards an inverse correlation with coronary microvascular dysfunction.

On the other hand, the SNP rs1799983_GT of eNOS was

  • confirmed to be an independent risk factor for microvascular dysfunction.

Our data suggest that the presence of certain genetic polymorphisms may represent a non-modifiable protective factor that could be used

  • to identify individuals at relatively low-risk for cardiovascular disease,
  • regardless of the presence of T2DM and dyslipidemia.

Current Clinical and Research Context

In normal coronary arteries, particularly the coronary microcirculation, there are several different mechanisms of CBFR, including

  • endothelial, neural, myogenic, and metabolic mediators [2, 8, 10, 12, 14, 15, 37, 55, 63, 64, 69].

In particular, endothelium-dependent vasodilation acts mainly via eNOS-derived nitric oxide (NO) in response to acetylcholine and shear stress.

  • NO increases intracellular cyclic guanosine monophosphate. It also causes vasodilation via
  • activation of both K-Ca channels and K-ATP channels.

Recent data suggested a pathophysiologically relevant role for the polymorphisms of eNOS/NOS3 in human coronary vasomotion [40–43]. Our data suggest that rs1799983_GT at exon 7 (Glu298Asp, GAG-GAT) of eNOS/NOS3 represents

  • an independent risk factor for coronary micro-vascular dysfunction, which agrees with a recent meta-analysis reporting an
  • association of this SNP with CAD in Asian populations [74]. In addition,
  • this SNP has been associated with endothelial dysfunction, although the mechanisms are not well defined [30].

Consistently, a recent study performed on 60 Indian patients with documented history of CAD reported a significantly higher frequency of rs1799983 (p.05) compared to control subjects, indicating that

  • variations in NOS3 gene may be useful clinical markers of endothelial dysfunction in CAD [54].
Interestingly, another association between rs1799983_GT and impaired collateral development has been observed in patientswith a

  • high-grade coronary stenosis or occlusion [19].
As is well known, the significance of the mechanisms of CBFR is partly determined by the location within the coronary vasculature. For instance, for vessels with a diameter of < 200 µm—which comprise the coronary microcirculation—metabolic regulation of coronary blood flow is considered the most important mechanism [24, 63]. Importantly, many of these mediators of metabolic regulation act through specific ion channels. In particular, in both coronary artery smooth muscle cells and endothelial cells
  • potassium channels determine the resting membrane potential (Em) and serve as targets of endogenous and therapeutic vasodilators [9, 27].
Several types of K+ channels are expressed in the coronary tree.
  • The K-ATP channels couple cell metabolic demand to conductance, via pore-forming (Kir6.1 and/or Kir6.2) subunits and regulatory
    [sulphonylurea-binding (SUR 1, 2A, or 2B)] subunits.
  • Kir6.x allows for channel inhibition by ATP, while SURx is responsible for channel activation by ADP and Mg2+.
K-ATP channel activation results in an outward flux of potassium and

  • consequent hyperpolarization, resulting in
  • voltage-gated calcium channel closure,
  • decreased Ca2+ influx, and ultimately
  • vasodilation [1, 5, 18, 20, 21, 33, 61, 62, 73, 75].

Our data do not support any significant difference regarding the Kir6.1 subunit of the K-ATP channel. On the other hand, this study suggests

  • an important role of specific SNPs for the Kir6.2 subunit (Tables 2, 3)—i.e., rs5215, rs5219, and rs5218—

in the susceptibility to IHD and microvascular dysfunction. These SNPs are among the most studied K-ATP channel polymorphisms, especially in the context of diabetes mellitus. In fact, in both Caucasian and Asian populations, these three SNPs as well as other genetic polymorphisms for the KCNJ11 gene have been associated with diabetes mellitus [34, 35, 44, 50, 57, 58, 70].

Nevertheless, the precise

  • structure–function impacts of the various amino acid substitutions remain unclear.

The rs5215 and rs5219 polymorphisms, also known as I337V and E23K, respectively, are highly linked with reported

  • concordance rates between 72 and 100 % [22, 23, 56].

The high concordance between rs5219 and rs5215 suggests that these polymorphisms

  • may have originated in a common ancestor, further indicating a
  • possible evolutionary advantage to their maintenance in the general population [49].

In our study, multivariate analysis suggests both an independent protective role of the

  • rs5215_GG against developing CAD and
  • a trend for rs5219_AA to be associated with protection against coronary microvascular dysfunction (Table 4a, b).
  • The variant rs5215_GG is a missense SNP located in the gene KCNJ11 at exon 1009 (ATC-GTC) and results in
    the substitution of isoleucine (I) residue with valine (V) [23].

Future studies are necessary to better understand the influence of this single amino acid variant on the function of the channel.

In humans, vasodilation of the coronary microvasculature in response to hypoxia and K-ATP channel opening
  • are both impaired in diabetes mellitus [39].
It is also described that gain-of-function mutations of the KCNJ11 gene cause neonatal diabetes mellitus, and loss-of-function mutations lead to congenital hyperinsulinism [43]. Our study is not discordant with previous studies about the correlation of SNPs of the Kir6.2 subunit and diabetes mellitus. Rather, our findings show that these SNPs are correlated with anatomically and functionally normal coronary arteries,
  • independent of the presence of either diabetes mellitus or dyslipidemia.
These data suggest the possibility that these particular SNPs may identify individuals with decreased risk for coronary microcirculatory dysfunction and IHD,
  • regardless of the presence of T2DM and/or dyslipidemia.

However, further studies are necessary to confirm these findings. In this context, to better investigate the implications of genetic variation in the K-ATP channel,

  • future studies should include ion channel’s functional modification due to the SNPs and analysis of SUR subunits.

More than 40-kV channel subunits have been identified in the heart, and sections of human coronary smooth muscle cells demonstrate Kv1.5 immunoreactivity [16, 17, 27, 38]. Through constant regulation of smooth muscle tone, Kv channels contribute to the control of coronary microvascular resistance [4, 7]. Pharmacologic molecules that inhibit Kv1.5 channels such as

  • pergolide [25],
  • 4-amino-pyridine [32], and
  • correolide [17]

lead to coronary smooth muscle cell contraction and block the coupling between

  • cardiac metabolic demand and
  • coronary blood flow.

However, no significant differences were identified between the study groups in terms of the particular polymorphisms for Kv1.5 that were analyzed in this study. Expression of

  • the voltage-dependent Na+ channel (Nav) has been demonstrated in coronary microvascular endothelia cells [3, 66].

Our analysis reveals a possible implication of the polymorphism rs1805124_GG for Nav1.5 channel with the presence of anatomically and functionally normal coronary arteries. This SNP leads to a homozygous 1673A-G transition, resulting in a His558-to-Arg (H558R) substitution. It is important to underline that

  • our data are the first to correlate the polymorphism rs1805124_GG with IHD.

Further research is necessary to confirm the observed implication.

Finally, we have analyzed the sarco/endoplasmic reticulum calcium transporting Ca2+-ATPase (SERCA), which is fundamental in the regulation of intracellular Ca2+ concentration [6].

SERCA is an intracellular pump that

  • catalyzes the hydrolysis of ATP coupled with the
  • translocation of calcium from the cytosol into the lumen of the sarcoplasmic reticulum.

Although this pump plays a critical role in regulation of the contraction/relaxation cycle, our analysis did not reveal any apparent association between

  • genetic variants of SERCA and the
  • prevalence of microvascular dysfunction or IHD.

Conclusions

This pilot study is the first to compare the prevalence of SNPs in genes encoding coronary ion channels between patients
  • with CAD or microvascular dysfunction and those with both anatomically and functionally normal coronary arteries.
Taken together, these results suggest the possibility of associations between SNPs and IHD and microvascular dysfunction, although

  • the precise manners by which specific genetic polymorphisms affect ion channel function and expression
have to be clarified by further research involving larger cohorts.

Limitations and future perspectives

Notable limitations of this pilot study are as follows:

1. Due to the lack of pre-existing data, the power calculation was performed in advance on the basis of assumptions of allele frequencies and the population at risk.
2. The sample size for each group is small, mainly due to both the difficulty in enrolling patients with normal coronary arteries and normal microvascular function (group 3) and the elevated costs of the supplies such as Doppler flow wires.
3. There is a lack of ethnic diversity of our cohort.
4. Currently, there is an absence of supportive findings in another independent cohort or population. However, our pilot study included patients within a well-defined, specific population and was aimed to identify the presence of statistical associations between selected genetic polymorphisms and the prevalence of a specific disease.
5. There is a lack of functional characterization of the described genetic polymorphisms.
6. We have not identified any correlation between novel SNPs and IHD. Nevertheless, we completely analyzed exon 3 of both KCNJ8 and KCNJ11 genes (Kir6.1 and Kir6.2 subunit, respectively) as well as the whole coding region of KCN5A gene (Kv1.5 channel).  Moreover, we examined previously described SNPs since there are no data in the literature regarding the possible association of the prevalences of those polymorphisms in the examined population.More extensive studies are necessary to confirm our  findings, possibly with a larger number of patients. Future investigations are also required to confirm the roles of ion  channels in the pathogenesis of coronary microvascular dysfunction and IHD. These studies should involve analysis of both other subunits of the K-ATP channels

  • sulfonylurea receptor, SURx and further coronary ion channels (e.g., calcium-dependent K channels), as well as
  • in vitro evaluation of ion channel activity by patch clamp and analysis of channel expression in the human cardiac tissue.

Moreover, to better address the significance of microvascular dysfunction in IHD, it could be interesting to analyze

  • typical atherosclerosis susceptibility genes (e.g., PPAP2B, ICAM1, et al.).

Methods

In this prospective, observational, single-center study - 242 consecutive patients admitted to our department were enrolled with

  • the indication to undergo coronary angiography .

All patients matched inclusion criteria

  1. age [18];
  2. suspected or documented diagnosis of acute coronary syndrome or stable angina
  3. with indication(s) for coronary angiography, in accordance with current guidelines [36, 68], and
  4. the same ethno-geographic Caucasian origin) and

Exclusion Criteria

  1. previous allergic reaction to iodine contrast,
  2. renal failure,
  3. simultaneous genetic disease,
  4. cardiogenic shock,
  5. non- ischemic cardiomyopathy

All patients signed an informed consent document  -

prior to participation in the study, which included

  • acknowledgement of the testing procedures to be performed
    (i.e., coronary angiography; intracoronary tests; genetic analysis, and processing of personal data).

The study was approved by the Institution’s Ethics Committee.
All clinical and instrumental characteristics were collected in a dedicated  database.

 Study Design

(a)  Standard therapies were administered, according to current guidelines [36, 68].
(b) An echocardiography was performed before and after coronary angiography
(c)  Coronary angiography was performed using radial artery or femoral artery
Judkins approach via sheath insertion.
(d) In patients showing normal epicardial arteries, intracoronary functional tests
were performed through Doppler flow wire to evaluate

  1. both endothelium-dependent microvascular function
    [via intracoronary (IC) infusion of acetylcholine (2.5–10 lg)] and
  2. nonendothelium-dependent microvascular function
    [via IC infusion of adenosine (5 lg)] [31]. 

(e) In all enrolled patients, a peripheral blood sample for genetic analysis was taken. 

On the basis  of the  coronary angiography and the intracoronary functional tests, 

  • the 242 patients were divided into three groups (see also Fig. 1).
  1. Group 1: 155 patients with anatomic coronary alteration
    (comprising patients with acute coronary syndrome and chronic stable angina).

    • microvascular dysfunction defined as coronary flow reserve (CFR) \ 2.5
    • after IC infusion of acetylcholine and adenosine].
  2. Group 2: 46 patients with functional coronary alteration
    [normal coronary arteries as assessed by angiography, and

    • as assessed by angiography and with normal functional tests
      (CFR C 2.5 after intracoronary infusion of acetylcholine and adenosine) (Fig. 1).
  3. Group 3: 41 patients with anatomically and functionally normal coronary arteries


BRC 2013 fedele genetic polymorphisms of ion channels.pdf_page_2

Fig. 1 Study design: 242 consecutive not randomized patients matching inclusion and exclusion criteria were enrolled.
In all patients, coronary angiography was performed, according to current ESC/ACC/AHA guidelines. In patients with
angiographically normal coronary artery, intracoronary functional tests were performed. In 242 patients
(155 with coronary artery disease, 46 patients with micro-vascular dysfunction, endothelium and/or non-endothelium
dependent, and 41 patients with anatomically and functionally normal coronary arteries) genetic analysis was performed.

Genetic Analysis

In conformity with the study protocol, ethylenediaminetetraacetic acid (EDTA) whole blood samples were collected according
to the international guidelines reported in the literature [48]. Samples were transferred to the Interinstitutional Multidisciplinary
BioBank (BioBIM) of IRCCS San Raffaele Pisana (Rome) and stored at -80 C until DNA extraction. Bibliographic research by
PubMed and web tools OMIM (http://www.ncbi.nlm.nih.gov/omim), Entrez SNP (http://www.ncbi.nlm.nih.gov/snp), and
Ensembl (http://www.ensembl.org/index.html) were used to select variants of genes involved in signaling pathways

  • related to ion channels and/or reported to be associated with
  • microvascular dysfunction and/or myocardial ischemia and/or
  • diseases correlated to IHD, such as diabetes mellitus.
Polymorphisms for the following genes were analyzed:
  1. NOS3 (endothelial nitric oxide synthase, eNOS),
  2. ATP2A2 (Ca2+/H+-ATPase pump, SERCA2),
  3. SCN5A (voltage-dependent Na+ channel,
  4. Nav1.5),
  5. KCNJ11 (ATP-sensitive K+ channel, Kir6.2 subunit),
  6. KCNJ8 (ATP-sensitive K+ channel, Kir6.1 subunit) and
  7. KCNA5 (voltage-gated K+ channel, Kv1.5).

In particular, we completely analyzed by direct sequencing

  • exon 3 of KCNJ8 (Kir6.1 subunit), which includes eight SNPs, as well as
  • the whole coding region of KCNA5 (Kv1.5 channel), which includes 32 SNPs and
  • four previously described variants [26, 47, 71, 72].
We also examined
  • the whole coding region of KCNJ11 (Kir6.2 subunit), for which sequence variants are described [26, 28].

All SNPs and sequence variants analyzed—a total of 62 variants of 6 genes—are listed in Table 1.

BRC 2013 fedele genetic polymorphisms of ion channels_page_004
BRC 2013 fedele genetic polymorphisms of ion channels_page_005

DNA was isolated from EDTA anticoagulated whole blood using the MagNA Pure LC instrument and theMagNA Pure LC
total DNA isolation kit I (Roche Diagnostics, Mannheim, Germany) according to the manufacturer’s instructions. Standard
PCR was performed in a GeneAmp PCR System 9700 (Applied Biosystems, CA) using HotStarTaq Master Mix
(HotStarTaq Master Mix Kit, QIAGEN Inc, CA). PCR conditions and primer sequences are listed in Table 1.

In order to exclude preanalytical and analytical errors, all direct sequencing analyses were carried out on both
strands using Big Dye Terminator v3.1 Cycle Sequencing kit
(Applied Biosystems), run on an ABI 3130
Genetic Analyzer (Applied Biosystems), and repeated on PCR products obtained from new nucleic acid extractions.
All data analyses were performed in a blind fashion.

Statistical Analysis

This report, intended as pilot study, is the first to compare

  • the prevalence of SNPs in genes encoding  several effectors (including ion channels)
  • involved in CBFR between these groups of patients.

No definite sample size could be calculated to establish a power analysis. groups of patients. However, assuming

  • a 15 % prevalence of normal  macrovascular and microvascular coronary findings in unselected patients
    undergoing coronary angiography,

we estimated that

  • a sample size of at least 150 patients could enable the computation of two-sided 95 % confidence intervals for
    • such prevalence estimates ranging between -5.0 and + 5.0 %.

The significance of the differences of observed alleles and genotypes between groups, as well as

  • analysis of multiple inheritance models for SNPs were also tested
    (co-dominant, dominant, recessive, over-dominant and log-additive)
  • using a free web-based application (http://213. 151.99.166/index.php?module=Snpstats)
  • designed from a genetic epidemiology  point of view to analyze association studies.

Akaike Information Criterion (AIC) was used to determine the best-fitting inheritance model for analyzed SNPs,

  • with the model with the lowest AIC reflecting the best balance of  goodness-of-fit and parsimony.

Moreover,  the allelic frequencies were estimated by gene counting, and the genotypes were scored. For each gene,

  • the observed numbers of each genotype were compared with those expected for a population in Hardy–Weinberg (HW) equilibrium
  • using a free web-based application  (http://213.151.99.166/index.php?module=Snpstats) [59].

Linkage disequilibrium coefficient (D0) and  haplotype analyses were assessed using  the  Haploview 4.1 program.
Statistical analysis was performed using SPSS software package for Windows v.16.0 (SPSS Inc., Chicago, IL).

All categorical variables are expressed as percentages, and all continuous variables as mean ± standard deviation.
Differences between categorical variables

  • were analyzed by Pearson’s Chi-SQ test.

Given the presence of three groups, differences  between continuous variables, were calculated using
(including the number of SNPs tested),

  • one-way ANOVA; a post-hoc analysis with Bonferroni correction was made for multiple comparisons.

Univariate and multivariate logistic regression analyses

  • the independent impact of genetic polymorphisms on
    • coronary artery disease and microvascular dysfunction,

were performed to assess the independent impact of

  • genetic polymorphisms on coronary artery disease
    and microvascular dysfunction
    ,

while adjusting for other confounding variables.  The following parameters were entered into the model:

  • age,
  • male gender,
  • type 2 diabetes mellitus (T2DM),
  • systemic arterial hypertension,
  • dyslipidemia,
  • smoking status, and
  • family history of myocardial infarction (MI).

Only variables with a p value < 0.10 after univariate analysis were entered

  • into the multivariable model as covariates.

A two-tailed p < 0.05 was considered statistically significant.

Definition of Cardiovascular Risk Factors

Patients were classified as having T2DM if they had

  • fasting levels of glucose of >126 mg/dL in two separate measurements or
  • if they were taking hypoglycemic drugs.

Systemic arterial hypertension was defined as

  • systolic blood pressure  > 140 mmHg / diastolic blood pressure > 90 mmHg
  • in two separate measurements or
  • if the patient was currently taking antihypertensive drugs.

Dyslipidemia was considered to be present if

  • serum cholesterol levels were>220 mg/dL or
  • if the patient was being treated with cholesterol-lowering drugs.

Family history of MI was defined as a first-degree relative with MI before the age of 60 years.

Results

Sixty-two polymorphisms distributed among six genes coding for
  • nitric oxide synthase,
  • the SERCA pump, and
  • ion channels
    • were screened for sequence variations using PCR amplification and
    • direct DNA sequencing analysis

in the population of

  • 155 patients with CAD (group 1),
  • 46 patients with microvascular dysfunction (group 2), and
  • 41 patients with normal coronary arteries and
    • normal endothelium dependent and endothelium-independent vasodilation (group 3).
In Group 3, the genotype distribution of

  • SNP rs5215 (Kir6.2/KCNJ11) moderately deviates from the HW equilibrium (p = 0.05).
In Group 1 (CAD), the polymorphism

  • rs6599230 of Nav1.5/SCN5A showed deviation from HW equilibrium (p = 0.017).
The genotypic distribution of groups in terms of polymorphisms for
  • eNOS/NOS3, SERCA/ATP2A2, Nav1.5/SCN5A, Kir6.1/KCNJ8, or Kv1.5/KCNA5
were noticed. However, significant differences (p.05) for the SNPs
  • rs5215_GG, and
  • rs5219_AA of Kir6.2/KCNJ11 were observed,
as shown in Table 2. 

Table 3 displays 
significant differences between normal subjects (group 3) and
  • patients with either CAD (group 1) or microvascular dysfunction (group 2).

BRC 2013 fedele genetic polymorphisms of ion channels_page_006

When correcting for other covariates as risk factors, the rs5215_GG genotype of Kir6.2/KCNJ11 was found to be 

  • significantly associated with CAD after multivariate analysis (OR = 0.319, p = 0.047, 95 % CI = 0.100–0.991), evidencing
  • a ‘‘protective’’ role of this genotype, as shown in Table 4a.

Similarly, a trend that supports this role of Kir6.2/KCNJ11 was also observed

  • in microvascular dysfunction for rs5219 AA. In contrast,
  • rs1799983_GT for eNOS/NOS3 was identified as an independent risk factor

following multivariate analysis (Table 4b), which agrees with literature findings as described below. 

BRC 2013 fedele genetic polymorphisms of ion channels_page_007

SOURCE for TABLES

BasicResCardiol(2013)108:387   http//dx.dio.org/10.1007/s00395-013-0387-4

Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

REFERENCES

1. Alekseev AE, Hodgson DM, Karger AB, Park S, Zingman LV, Terzic A (2005) ATP-sensitive K? channel channel/enzyme multimer: metabolic gating in the heart. J Mol
Cell Cardiol 38:895–905. doi:10.1016/j.yjmcc.2005.02.022
2. Baumgart D, Naber C, Haude M, Oldenburg O, Erbel R, Heusch G, Siffert W (1999) G protein beta3 subunit 825T allele and enhanced coronary vasoconstriction on
alpha(2)-adrenoceptor activation. Circ Res 85:965–969. doi:10.1161/01.RES.85.10.965
3. Belardinelli L, Shryock JC, Fraser H (2006) Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor
ranolazine. Heart 92:6–14. doi:10.1136/hrt.2005.078790
4. Berwick ZC, Moberly SP, Kohr MC, Morrical EB, Kurian MM, Dick GM, Tune JD (2012) Contribution of voltage-dependent K+ and Ca2+ channels to coronary pressure-
flow autoregulation. Basic Res Cardiol 107:264. doi:10.1007/s00395-012-0264-6
5. Brayden JE (2002) Functional roles of KATP channels in vascular smooth muscle. Clin Exp Pharmacol Physiol 29:312–316. doi:10.1046/j.1440-1681.2002.03650.x
6. Brini M, Carafoli E (2009) Calcium pumps in health and disease. Physiol Rev 89:1341–1378. doi:10.1152/physrev.00032.2008
7. Chen TT, Luykenaar KD, Walsh EJ, Walsh MP, Cole WC (2006) Key role of Kv1 channels in vasoregulation. Circ Res 99:53–60. doi:10.1161/01.RES.0000229654.45090.57
8. Cohen KD, Jackson WF (2005) Membrane hyperpolarization is not required for sustained muscarinic agonist-induced increases in intracellular Ca2+ in arteriolar endothelial
cells. Microcirculation 12:169–182. doi:10.1080/10739680590904973
9. Daut J, Maier-Rudolph W, von Beckerath N, Mehrke G, Gu¨nter K, Goedel-Meinen L (1990) Hypoxic dilation of coronary arteries is mediated by ATP-sensitive potassium
channels. Science 247:1341–1344. doi:10.1126/science.2107575
10. Davidson SM, Duchen MR (2007) Endothelial mitochondria: contributing to vascular function and disease. Circ Res 100:1128–1141. doi:10.1161/01.RES.0000261970.18328.1d
…. 75

SOURCE for References 1-75

Basic Res Cardiol (2013) 108:387   http://dx.doi.org/10.1007/s00395-013-0387-4

Other related articles published on this Open Access Online Scientific Journal include the following: 

ION CHANNEL and Cardiovascular Diseases

http://pharmaceuticalintelligence.com/?s=Ion+Channel

Calcium Role in Cardiovascular Diseases

Part I: Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-cytoskeleton/

Part II: Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/26/role-of-calcium-the-actin-skeleton-and-lipid-structures-in-signaling-and-cell-motility/

Part III: Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease

Larry H. Bernstein, MD, FCAP, Stephen J. Williams, PhD
 and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/02/renal-distal-tubular-ca2-exchange-mechanism-in-health-and-disease/

Part IV: The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/08/the-centrality-of-ca2-signaling-and-cytoskeleton-involving-calmodulin-kinases-and-ryanodine-receptors-in-cardiac-failure-arterial-smooth-muscle-post-ischemic-arrhythmia-similarities-and-differen/

Part V: Ca2+-Stimulated Exocytosis:  The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone and Neurotransmitter

Larry H Bernstein, MD, FCAP
and
Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/23/calmodulin-and-protein-kinase-c-drive-the-ca2-regulation-of-hormone-and-neurotransmitter-release-that-triggers-ca2-stimulated-exocytosis/

Part VI: Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/

Part VII: Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias-and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related-contractile/

Part VIII: Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/12/disruption-of-calcium-homeostasis-cardiomyocytes-and-vascular-smooth-muscle-cells-the-cardiac-and-cardiovascular-calcium-signaling-mechanism/

Part IX: Calcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/16/calcium-channel-blocker-calcium-as-neurotransmitter-sensor-and-calcium-release-related-contractile-dysfunction-ryanopathy/

Part X: Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/10/synaptotagmin-functions-as-a-calcium-sensor-how-calcium-ions-regulate-the-fusion-of-vesicles-with-cell-membranes-during-neurotransmission/

Part XI: Sensors and Signaling in Oxidative Stress

Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/11/01/sensors-and-signaling-in-oxidative-stress/

Part XII: Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/21/genetic-polymorphisms-of-ion-channels-have-a-role-in-the-pathogenesis-of-coronary-microvascular-dysfunction-and-ischemic-heart-disease/

Mitochondria and Oxidative Stress Role in Cardiovascular Diseases

Reversal of Cardiac Mitochondrial Dysfunction

Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/04/14/reversal-of-cardiac-mitochondrial-dysfunction/

Calcium Signaling, Cardiac Mitochondria and Metabolic Syndrome

Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/11/09/calcium-signaling-cardiac-mitochondria-and-metabolic-syndrome/

Mitochondrial Dysfunction and Cardiac Disorders

Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-dysfunction-and-cardiac-disorders/

Mitochondrial Metabolism and Cardiac Function

Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/

Mitochondria and Cardiovascular Disease: A Tribute to Richard Bing

Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/04/14/chapter-5-mitochondria-and-cardiovascular-disease/

MIT Scientists on Proteomics: All the Proteins in the Mitochondrial Matrix Identified

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/02/03/mit-scientists-on-proteomics-all-the-proteins-in-the-mitochondrial-matrix-identified/

Mitochondrial Dynamics and Cardiovascular Diseases

Ritu Saxena, Ph.D.

http://pharmaceuticalintelligence.com/2012/11/14/mitochondrial-dynamics-and-cardiovascular-diseases/

Mitochondrial Damage and Repair under Oxidative Stress

Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/

Nitric Oxide has a Ubiquitous Role in the Regulation of Glycolysis -with a Concomitant Influence on Mitochondrial Function

Larry H. Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with-a-concomitant-influence-on-mitochondrial-function/

Mitochondrial Mechanisms of Disease in Diabetes Mellitus

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2012/08/01/mitochondrial-mechanisms-of-disease-in-diabetes-mellitus/

Mitochondria Dysfunction and Cardiovascular Disease – Mitochondria: More than just the “Powerhouse of the Cell”

Ritu Saxena, PhD

http://pharmaceuticalintelligence.com/2012/07/09/mitochondria-more-than-just-the-powerhouse-of-the-cell/

Read Full Post »


PROGRAM ANNOUNCEMENT

Conference Program is available at

http://www.sachsforum.com/newyork14/


Event’s agenda available at:
http://www.sachsforum.com/newyork14/newyork14-agenda.html

Wednesday, 19th March 2014
Registration and coffee begins – 08.00
Program begins – 08.15
Networking reception will take place at 18.00 – 20.00

Once you arrive at 7 World Trade Center (250 Greenwich St, New York, NY10007, USA).
Please use the D Elevator Bank to the 40th floor where Sachs Team will welcome you at the registration desk.

For urgent issues, please contact:
Tomas@sachsforum.com (cell number +44 77 043 158 71)
Or Mina@sachsforum.com (cell number +44 74 636 695 04) Cells available from 15th March.

Announcement

LEADERS IN PHARMACEUTICAL BUSINESS INTELLIGENCE will cover the event for the Scientific Media

Dr. Lev-Ari will be in attendance on 3/19/2014 at 

The New York Academy of Sciences.

Editorials of event coverage via our 

Open Access Scientific Journal

http://pharmaceuticalintelligence.com

Date             Views to Date      # of articles      “NIH Clicks”  “Nature Clicks”

3/05/2014      338,958                 1,717                 1,830                   965

  • 369 Articles on Cancer
  • 74 articles on Imaging-based Cancer Patient Management

http://pharmaceuticalintelligence.com/?s=Cancer+

  • Cancer e-Book

Series C: e-Books on Cancer & Oncology

Series C Content Consultant: Larry H. Bernstein, MD, FCAP 

VOLUME ONE 

Cancer Biology and Genomics for Disease Diagnosis

2014

Stephen J. Williams, PhD, Senior Editor

sjwilliamspa@comcast.net

Tilda Barliya, PhD, Editor

tildabarliya@gmail.com

Ritu Saxena, PhD, Editor

ritu.uab@gmail.com

http://pharmaceuticalintelligence.com/biomed-e-books/series-c-e-books-on-cancer-oncology/cancer-biology-and-genomics-for-disease-diagnosis/

SIX SOURCES of INVESTMENT for BioMed INVENTIONS

Curator: Aviva Lev-Ari, PhD, RN

Investing and inventing: Is the Tango of Mars and Venus Still on

MEDIA COVERAGE

The Event will be broadcasted via our distributions channels on the Internet and all Search Engines featuring WordPress.com

  • Scientific Journal

http://pharmaceuticalintelligence.com

http://pharmaceuticalintelligence.com/2014/03/05/milestone-for-our-venture-we-celebrate-our-top-authors-by-number-of-articles-in-the-journal-to-date-1000-301-58-49-46-43-40-28-20/

  • Facebook HomePage of LEADERS IN PHARMACEUTICAL BUSINESS INTELLIGENCE

http://www.facebook.com/LeadersInPharmaceuticalBusinessIntelligence

  • On Twitter.com  @pharma_BI

http://twitter.com/pharma_BI

  • 53 BioMed Groups on LinkedIn.com

http://www.linkedin.com/in/avivalevari

  • Dr. Lev-Ari’s BioMed Group launched by and managed by on LinkedIn.com – LEADERS IN PHARMACEUTICAL BUSINESS INTELLIGENCE

http://www.linkedin.com/groups?gid=4346921&trk=hb_side_g

2nd ANNUAL

Sachs Cancer Bio Partnering &
Investment Forum

Promoting Public & Private Sector Collaboration & Investment

in Drug Development

19th March 2014 • New York Academy of Sciences • USA  
spi2012

http://www.sachsforum.com/newyork14/

 

The 2nd Annual Sachs Cancer Bio Partnering & Investment Forum is designed to bring together thought leaders from cancer research institutes, patient advocacy groups, pharma and biotech to facilitate partnering and funding/investment. We expect around 200 delegates and there is an online meeting system and meeting facilities to make the event transactional. There will also be a track of about 30 presentations by listed and private biotechnology companies seeking licensing/investment.

divider

The 2nd Annual Sachs Cancer Bio Partnering & Investment Forum will cover the following topics in the program:

  • Advances in Translational Research
  • Strategies for Small Molecule and Biologicals Drug Development
  • Deal Making
  • Public & Private Partnerships
  • Diagnostics
  • Immunotherapies and Cancer Vaccines
  • Case Study

Confirmed Speakers & Chairs include:
Anne Altmeyer, Executive Director Business Development & LicensingNovartis Pharmaceuticals
Ariel Jasie, Executive Director of Business DevelopmentCelgene
Beth Jacobs, Managing PartnerExcellentia Global Partners
Boris Peaker, Executive Director, Biotechnology Equity ResearchOppenheimer & Co. Inc.
Carole Nuechterlein, Head Roche Venture FundF.Hoffmann-La Roche AG Roche Venture Fund
Dan Snyder, President and COOMolecularMD
Daryl Mitteldorf, Executive DirectorGlobal Prostate Cancer Alliance
Dennis Purcell, Senior Managing PartnerAisling Capital
Doug Plessinger, Vice President of Clinical and Medical AffairsArgos Therapeutics, Inc.
Elizabeth Bachert, Senior Director Worldwide Business DevelopmentPfizer
Esteban Pombo-Villar, COOOxford BioTherapeutics AG
Florian Schodel, CEO, Philimmune LLC
Frederick Cope, President and CSONavidea Biopharmaceuticals
Guillaume Vignon, Director of Global BD Oncology, Merck Serono SA
Harren Jhoti, PresidentAstex Pharmaceuticals Inc.
Harry Glorikan, Managing DirectorPrecision for Medicine
James Mulé, Executive Vice President and Associate Center Director for Translational Research,
H Lee Moffit Cancer Center
Keith Knutson, Program Director and Principal Investigator of the Cancer Vaccines and immune Therapies ProgramVaccine and Gene Therapy Institute of Florida
Kevin DeGeeter, AnalystLadenburg Thalmann & Co, Inc.
Klaus Urbahns, Head, Discovery TechnologiesMerck Serono
Kristina Khodova, Project Manager, OncologySkolkovo Foundation
Lorenza Castellon, Business Development ConsultantSuda Ltd.
Louis DeGennaro, Executive VP, CMO, The Leukemia and Lymphoma Society
Louise Perkins, Chief Science OfficerMelanoma Research Alliance
Mara Goldstein, Managing Director, Senior Healthcare AnalystCantor Fitzgerald
Michael Goldberg, Managing PartnerMontaur Capital
Nathan Tinker, Executive DirectorNewYorkBIO
Nicholas Dracopoli, Vice President and Head of OncologyJanssen Research & Development
Peter Hoang, Managing Director, Office of Innovations, Technology Based VenturesThe University of Texas MD Anderson Cancer Center
Philip Gotwals, Executive Director, Oncology Research CollaborationsNovartis Institutes for BioMedical Research
Robert Petit, CSOAdvaxis Inc.
Stephen Brozak, Managing Partner and PresidentWBB Securities, LLC
Steven Tregay, CEOForma Therapeutics
Steven W. Young, PresidentAddario lung Cancer Medical Institute
Stuart Barich, Managing Director, Healthcare Investment BankingOppenheimer & Company
Tariq Kassum MD, Vice President, Business Development and StrategyMillennium Pharmaceuticals
TBC, Cardinal Health
TBC, UCSD
Timothy Herpin, Vice President, Head of Transactions (UK), Business DevelopmentAstraZeneca
Vikas Sharma, Director, Business DevelopmentRexahn Pharmaceuticals, Inc.
Walter Capone, PresidentThe Multiple Myeloma Research Foundation

View the full list of 2013 Forum Speakers & Chairs >>

divider

Presenting Opportunities for Biotech, Pharmaceutical companies  and Patient Advocacy Groups

Presenting at the forum offers excellent opportunities to showcase activities and highlight investment and partnership opportunities. Biotech companies will be able to communicate investment and licensing opportunities. These are for both public and private companies. The audience is comprised of financial and industry investors. These are streamed 15 minute presentations. The patient advocacy presentations are 30 minutes.

Sachs forums are recognised as the leading international stage for those interested in investing in the biotech and life science industry and are highly transactional. They draw together an exciting cross-section of early-stage/pre-IPO, late-stage and public companies with leading investors, analysts, money managers and pharmas. The Boston forum provides the additional interaction with the academic/scientific and patient advocacy communities.

Sponsorship and Exhibition

Sachs Associates has developed an extensive knowledge of the key individuals operating within the European and global biotech industry. This together with a growing reputation for excellence puts Sachs Associates at the forefront of the industry and provides a powerful tool by which to increase the position of your company in this market.

Raise your company’s profile directly with your potential clients. All of our sponsorship packages are tailor made to each client, allowing your organisation to gain the most out of attending our industry driven events.

To learn more about presenting, exhibition or sponsorship opportunities, please contact
Mina Orda + 44 (0)203 463 4890 or by email: Mina Orda.

 

spi2012
Register Now
Register
To Exhibit
Register
To Present
OVERVIEW sachs Speakers sachs Presenting Companies sachs Attendees sachs Program sachs Sponsors / Supporters sachs Venue sachs Accommodation
Biotech i Europe Investor Forum
sachs sachs
Companies Who Presented at the 2013 Forum Included:
Aileron Therapeutics, Inc.
AnaptysBio, Inc
Argos Therpeutics, Inc
Atossa Genetics
BioCancell Ltd.
BioLineRx Ltd.
Cellectis
CENTROSE
Churchill Pharmaceuticals
Constellation Pharmaceuticals
CureVac GmbH
Dicerna Pharmaceuticals
Etubics Corporation
Genisphere
immatics biotechnologies GmbH
ImmunoGen, Inc
Life Science Nation
MacroGenics, Inc
Melanovus Oncology
MiNA Therapeutics
MolecularMD
Oncolix, Inc.
OncoSec Medical Incorporated
Oxford BioTherapeutics
RAMOT at Tel Aviv University
Rescue Therapeutics, Inc.
Sialix, Inc.
Sorrento Therapeutics
to-BBB technologies BV
TVAX Biomedical, Inc.
The 2nd Annual Sachs Cancer Bio Partnering & Investment Forum is designed to bring together thought leaders from cancer research institutes, patient advocacy groups, pharma and biotech to facilitate partnering and funding/investment. We expect around 200 delegates and there is an online meeting system and meeting facilities to make the event transactional. There will also be a track of about 30 presentations by listed and private biotechnology companies seeking licensing/investment.dividerThe 2nd Annual Sachs Cancer Bio Partnering & Investment Forum will cover the following topics in the program:

  • Advances in Translational Research
  • Strategies for Small Molecule and Biologicals Drug Development
  • Deal Making
  • Public & Private Partnerships

Confirmed Speakers & Chairs include:

The 2nd Annual Sachs Cancer Bio Partnering & Investment Forum will cover the following topics in the program:

  • Advances in Translational Research
  • Strategies for Small Molecule and Biologicals Drug Development
  • Deal Making
  • Public & Private Partnerships
  • Diagnostics
  • Immunotherapies and Cancer Vaccines

Confirmed Speakers & Chairs include:
Anne Altmeyer, Executive Director Business Development & LicensingNovartis Pharmaceuticals
Ariel Jasie, Executive Director of Business DevelopmentCelgene
Beth Jacobs, Managing PartnerExcellentia Global Partners
Boris Peaker, Executive Director, Biotechnology Equity ResearchOppenheimer & Co. Inc.
Carole Nuechterlein, Head Roche Venture FundF.Hoffmann-La Roche AG Roche Venture Fund
Daryl Mitteldorf, Executive DirectorGlobal Prostate Cancer Alliance
Dennis Purcell, Senior Managing PartnerAisling Capital
Doug Plessinger, Vice President of Clinical and Medical AffairsArgos Therapeutics, Inc.
Elizabeth Bachert, Senior Director Worldwide Business DevelopmentPfizer
Esteban Pombo-Villar, COOOxford BioTherapeutics AG
Florian Schodel, CEO, Philimmune LLC
Guillaume Vignon, Director of Global BD Oncology, Merck Serono SA
Harren Jhoti, PresidentAstex Pharmaceuticals Inc.
Harry Glorikan, Managing DirectorPrecision for Medicine
James Mulé, Executive Vice President and Associate Center Director for Translational Research,
H Lee Moffit Cancer Center
Keith Knutson, Program Director and Principal Investigator of the Cancer Vaccines and immune Therapies ProgramVaccine and Gene Therapy Institute of Florida
Klaus Urbahns, Head, Discovery TechnologiesMerck Serono
Kristina Khodova, Project Manager, OncologySkolkovo Foundation
Lorenza Castellon, Business Development ConsultantSuda Ltd.
Louis DeGennaro, Executive VP, CMO, The Leukemia and Lymphoma Society
Louise Perkins, Chief Science OfficerMelanoma Research Alliance
Mara Goldstein, Managing Director, Senior Healthcare AnalystCantor Fitzgerald
Nathan Tinker, Executive DirectorNewYorkBIO
Nicholas Dracopoli, Vice President and Head of OncologyJanssen Research & Development
Peter Hoang, Managing Director, Office of Innovations, Technology Based VenturesThe University of Texas MD Anderson Cancer Center
Philip Gotwals, Executive Director, Oncology Research CollaborationsNovartis Institutes for BioMedical Research
Robert Petit, CSOAdvaxis Inc.
Steven Tregay, CEOForma Therapeutics
Steven W. Young, PresidentAddario lung Cancer Medical Institute
Stuart Barich, Managing Director, Healthcare Investment BankingOppenheimer & Company
Tariq Kassum MD, Vice President, Business Development and StrategyMillennium Pharmaceuticals
Timothy Herpin, Vice President, Head of Transactions (UK), Business DevelopmentAstraZeneca
Walter Capone, PresidentThe Multiple Myeloma Research Foundation

_______

View the full list of 2013 Forum Speakers & Chairs >>

dividerPresenting Opportunities for Biotech, Pharmaceutical companies  and Patient Advocacy Groups

Presenting at the forum offers excellent opportunities to showcase activities and highlight investment and partnership opportunities. Biotech companies will be able to communicate investment and licensing opportunities. These are for both public and private companies. The audience is comprised of financial and industry investors. These are streamed 15 minute presentations. The patient advocacy presentations are 30 minutes.

Sachs forums are recognised as the leading international stage for those interested in investing in the biotech and life science industry and are highly transactional. They draw together an exciting cross-section of early-stage/pre-IPO, late-stage and public companies with leading investors, analysts, money managers and pharmas. The Boston forum provides the additional interaction with the academic/scientific and patient advocacy communities.

Sponsorship and Exhibition

Sachs Associates has developed an extensive knowledge of the key individuals operating within the European and global biotech industry. This together with a growing reputation for excellence puts Sachs Associates at the forefront of the industry and provides a powerful tool by which to increase the position of your company in this market.

Raise your company’s profile directly with your potential clients. All of our sponsorship packages are tailor made to each client, allowing your organisation to gain the most out of attending our industry driven events.

To learn more about presenting, exhibition or sponsorship opportunities, please contact
Mina Orda + 44 (0)203 463 4890 or by email: Mina Orda.

SOURCE

http://www.sachsforum.com/newyork14/index.html

From: Mina@sachsforum.com
To: AvivaLev-Ari@alum.berkeley.edu
Sent: Mon Dec 16 12:01:21 UTC 2013

From: Tomas Andrulionis <Tomas@sachsforum.com>
Date: Tue, 10 Dec 2013 16:13:53 +0000
To: “avivalev-ari@alum.berkeley.edu” <avivalev-ari@alum.berkeley.edu>
Conversation: Complimentary Invitation for the 2nd Annual Sachs Cancer Bio Partnering & Investment Forum, 19th March 2014, New York Academy of Sciences

Read Full Post »


Genetics of Hypertension in African Americans – Gene Association Study

Reporter: Aviva Lev-Ari, PhD, RN

Genome-Wide Association Study of Cardiac Structure and Systolic Function in African Americans – The Candidate Gene Association Resource (CARe) Study

Ervin R. Fox, MD*Solomon K. Musani, PhD*Maja Barbalic, PhD*Honghuang Lin, PhD, Bing Yu, MS, Kofo O. Ogunyankin, MD, Nicholas L. Smith, PhD, Abdullah Kutlar, MD, Nicole L. Glazer, MD, Wendy S. Post, MD, MS, Dina N. Paltoo, PhD, MPH, Daniel L. Dries, MD, MPH, Deborah N. Farlow, PhD, Christine W. Duarte, PhD, Sharon L. Kardia, PhD, Kristin J. Meyers, PhD, Yan V. Sun, PhD, Donna K. Arnett, PhD, Amit A. Patki, MS, Jin Sha, MS, Xiangqui Cui, PhD, Tandaw E. Samdarshi, MD, MPH, Alan D. Penman, PhD, Kirsten Bibbins-Domingo, MD, PhD, Petra Bůžková, PhD, Emelia J. Benjamin, MD, David A. Bluemke, MD, PhD, Alanna C. Morrison, PhD, Gerardo Heiss, MD, J. Jeffrey Carr, MD, MSc, Russell P. Tracy, PhD, Thomas H. Mosley, PhD, Herman A. Taylor, MD, Bruce M. Psaty, MD, PhD, Susan R. Heckbert, MD, PhD, Thomas P. Cappola, MD, ScM and Ramachandran S. Vasan, MD

Author Affiliations

Guest Editor for this article was Barry London, MD, PhD.

Correspondence to Ervin Fox, MD MPH, FAHA, FACC, Professor of Medicine, Department of Medicine, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216. E-mail efox@medicine.umsmed.edu

* These authors contributed equally as joint first authors.

Abstract

Background—Using data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study.

Methods and Results—Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×107). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×107) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×107) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×108) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×107) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN.

Conclusions—In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.

SOURCE:

Circulation: Cardiovascular Genetics. 2013; 6: 37-46

Published online before print December 28, 2012,

doi: 10.1161/ CIRCGENETICS.111.962365

 

Read Full Post »


Erythropoietin (EPO) and Intravenous Iron (Fe) as Therapeutics for Anemia in Severe and Resistant CHF: The Elevated N-terminal proBNP Biomarker

 

Co-Author of the FIRST Article: Larry H. Bernstein, MD, FCAP

Reviewer and Curator of the SECOND and of the THIRD Articles: Larry H. Bernstein, MD, FCAP

and

Article Architecture Curator: Aviva Lev-Ari, PhD, RN

This article presents Advances in the Treatment using Subcutaneous Erythropoietin (EPO) and Intravenous Iron (Fe) for IMPROVEMENT of Severe and Resistant Congestive Heart Failure and its resultant Anemia.  The Leading Biomarker for Congestive Heart Failure is an Independent Predictor identified as an Elevated N-terminal proBNP.

NT-proBNP schematic diagram-Copy.pdf_page_1

FIRST ARTICLE

Anemia as an Independent Predictor of Elevated N-terminal proBNP

Salman A. Haq, MD1, Mohammad E. Alam2, Larry Bernstein, MD, FCAP3,  LB Banko 1, Leonard Y. Lee, MD, FACS4, Barry I. Saul, MD, FACC5, Terrence J. Sacchi, MD, FACC6,  John F. Heitner, MD, FACC7
1Cardiology Fellow,  2  Clinical Chemistry Laboratories, 3 Program Director, Cardiothoracic Surgery, 4 Division of Cardiology,  Department of Medicine, New York Methodist Hospital-Weill Cornell, Brooklyn, NY

(Unpublished manuscript)  Poster Presentation

SECOND ARTICLE

The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study

Donald S Silverberg, MDa; Dov Wexler, MDa; David Sheps, MDa; Miriam Blum, MDa; Gad Keren, MDa; Ron Baruch, MDa; Doron Schwartz, MDa; Tatyana Yachnin, MDa; Shoshana Steinbruch, RNa; Itzhak Shapira, MDa; Shlomo Laniado, MDa; Adrian Iaina, MDa

J Am Coll Cardiol. 2001;37(7):1775-1780. doi:10.1016/S0735-1097(01)01248-7

http://content.onlinejacc.org/article.aspx?articleid=1127229

THIRD ARTICLE

The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations

Donald S Silverberg, MDa; Dov Wexler, MDa; Miriam Blum, MDa; Gad Keren, MDa; David Sheps, MDa; Eyal Leibovitch, MDa; David Brosh, MDa; Shlomo Laniado, MDa; Doron Schwartz, MDa; Tatyana Yachnin, MDa; Itzhak Shapira, MDa; Dov Gavish, MDa; Ron Baruch, MDa; Bella Koifman, MDa; Carl Kaplan, MDa; Shoshana Steinbruch, RNa; Adrian Iaina, MDa

J Am Coll Cardiol. 2000;35(7):1737-1744. doi:10.1016/S0735-1097(00)00613-6

http://content.onlinejacc.org/article.aspx?articleid=1126474

Perspective

This THREE article sequence is related by investigations occurring by me, a very skilled cardiologist and his resident, and my premedical student at New York Methodist Hospital-Weill Cornell, in Brooklyn, NY, while a study had earlier been done applying the concordant discovery, which the team in Israel had though was knowledge neglected.  There certainly was no interest in the problem of the effect of anemia on the patient with severe congestive heart failure, even though erythropoietin was used widely in patients with end-stage renal disease requiring dialysis, and also for patients with myelofibrosis.  The high cost of EPO was only one factor, the other being a guideline to maintain the Hb concentration at or near 11 g/dl – not higher.  In the first article, the authors sought to determine whether the amino terminal pro– brain type natriuretic peptide (NT-pro BNP) is affected by anemia, and to determine that they excluded all patients who had renal insufficiency and/or CHF, since these were associated with elevated NT-proBNP.  It was already well established that this pro-peptide is secreted by the heart with the action as a urinary sodium retention hormone on the kidney nephron, the result being an increase in blood volume.  Perhaps the adaptation would lead to increased stroke volume from increased venous return, but that is not conjectured.  However, at equilibrium, one would expect there to be increased red cell production to maintain the cell to plasma volume ratio, thereby, resulting in adequate oxygen exchange to the tissues.  Whether that is always possible is uncertain because any reduction in the number of functioning nephrons would make the kidney not fully responsive at the Na+ exchange level, and the NT-pro BNP would rise.  This introduces complexity into the investigation, requiring a removal of confounders to establish the effect of anemia.

The other two articles are related studies by the same group in Israel.  They surmised that there was evidence that was being ignored as to the effect of anemia, and the treatment of anemia was essential in addition to other treatments.  They carried out a randomized trial to determine just that, a benefit to treating the anemia.  But they also conjectured that an anemia with a Hb concentration below 12 g/dl has an deleterious effect on the targeted population.  Treatment by intermittent transfusions could potentially provide the added oxygen-carrying capacity, but the fractionation of blood, the potential for transfusion-transmitted disease and transfusion-reactions, combined with the need for the blood for traumatic blood loss made EPO a more favorable alternative to packed RBCs.  The proof-of-concept is told below.  Patients randomized to receive EPO at a lower than standard dose + iron did better.

 

Introduction

In this article, Erythropoietin (EPO) and Intravenous Iron (Fe) as Therapeutics for Anemia in Severe and Resistant CHF: The Elevated N-terminal proBNP Biomarker we provides a summary of three articles on the topic and we shading new light on the role that Anemia Hb < 12 g%  plays as a Biomarker for CHF and for

  • prediction of elevated BNP, known as an indicator for the following Clinical Uses:
Clinical Use
  • Rule out congestive heart failure (CHF) in symptomatic individuals
  • Determine prognosis in individuals with CHF or other cardiac disease
  • Maximize therapy in individuals with heart failure by the use of Subcutaneous Erythropoietin (EPO) and Intravenous Iron (Fe)
Evaluation of BNP and NT-proBNP Clinical Performance
Study Sensitivity(%) Specificity(%) PPV(%) NPV(%)
Diagnose impaired LVEF3
BNP 73 77 70 79
NT-proBNP 70 73 61 80
Diagnose LV systolic dysfunction after MI2
BNP 68 69 56 79
NT-proBNP 71 69 56 80
Diagnose LV systolic dysfunction after MI12
BNP 94 40 NG 96
NT-proBNP 94 37 NG 96
Prognosis in newly diagnosed heart failure patients: prediction of mortality/survival1
BNP 98 22 42 94
NT-proBNP 95 37 47 93
Prognosis post myocardial infarction: prediction of mortality2
BNP 86 72 39 96
NT-proBNP 91 72 39 97
Prognosis post myocardial infarction: prediction of heart failure2
BNP 85 73 54 93
NT-proBNP 82 69 50 91
PPV, positive predictive value; NPV, negative predictive value; LVEF, left ventricular ejection fraction; NG, not given.
Reference Range
BNP: < 100 pg/mL13
proBNP, N-terminal: 300 pg/mL
The NT-proBNP reference range is based on EDTA plasma. Other sample types will produce higher values.
Interpretive Information
Symptomatic patients who present with a BNP or NT-proBNP level within the normal reference range are highly unlikely to have CHF. Conversely, an elevated baseline level indicates the need for further cardiac assessment and indicates the patient is at increased risk for future heart failure and mortality.BNP levels increase with age in the general population, with the highest concentrations seen in those greater than 75 years of age.14 Heart failure is unlikely in individuals with a BNP level <100 pg/mL and proBNP level ≤300 pg/mL. Heart failure is very likely in individuals with a BNP level >500 pg/mL and proBNP level ≥450 pg/mL who are <50 years of age, or ≥900 pg/mL for patients ≥50 years of age. Patients in between are either hypertensive or have mild ischemic or valvular disease and should be observed closely.15BNP is increased in CHF, left ventricular hypertrophy, acute myocardial infarction, atrial fibrillation, cardiac amyloidosis, and essential hypertension. Elevations are also observed in right ventricular dysfunction, pulmonary hypertension, acute lung injury, subarachnoid hemorrhage, hypervolemic states, chronic renal failure, and cirrhosis.NT-proBNP levels are increased in CHF, left ventricular dysfunction, myocardial infarction, valvular disease, hypertensive pregnancy, and renal failure, even after hemodialysis.Although levels of BNP and NT-proBNP are similar in normal individuals, NT-proBNP levels are substantially greater than BNP levels in patients with cardiac disease due to increased stability (half-life) of NT-proBNP in circulation. Thus, results from the two tests are not interchangeable.
References
  1. Cowie MR and Mendez GF. BNP and congestive heart failure. Prog Cardiovasc Dis. 2002;44:293-321.
  2. Richards AM, Nicholls MG, Yandle TG, et al. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin. New neurohormonal predictors of left ventricular function and prognosis after myocardial infarction. Circulation. 1998:97:1921-1929.
  3. Hammerer-Lercher A, Neubauer E, Muller S, et al. Head-to-head comparison of N-terminal pro-brain natriuretic peptide, brain natriuretic peptide and N-terminal pro-atrial natriuretic peptide in diagnosing left ventricular dysfunction. Clin Chim Acta. 2001;310:193-197.
  4. McDonagh TA, Robb SD, Murdoch DR, et al. Biochemical detection of left-ventricular systolic dysfunction. Lancet. 1998;351:9-13.
  5. Mukoyama Y, Nakao K, Hosoda K, et al. Brain natriuretic peptide as a novel cardiac hormone in humans: Evidence for an exquisite dual natriuretic peptide system, ANP and BNP. J Clin Invest. 1991;87:1402-1412.
  6. Hunt PJ, Richards AM, Nicholls MG, et al. Immunoreactive amino-terminal pro-brain natriuretic peptide (NT-PROBNP): a new marker of cardiac impairment. Clin Endocrinol. 1997;47:287-296.
  7. Davis M, Espiner E, Richards G, et al. Plasma brain natriuretic peptide in assessment of acute dyspnoea. Lancet. 1994;343:440-444.
  8. Kohno M, Horio T, Yokokawa K, et al. Brain natriuretic peptide as a cardiac hormone in essential hypertension. Am J Med. 1992;92:29-34.
  9. Bettencourt P, Ferreira A, Pardal-Oliveira N, et al. Clinical significance of brain natriuretic peptide in patients with postmyocardial infarction. Clin Cardiol. 2000;23:921-927.
  10. Jernberg T, Stridsberg M, Venge P, et al. N-terminal pro brain natriuretic peptide on admission for early risk stratification of patients with chest pain and no ST-segment elevation. J Am Coll Cardiol. 2002;40:437-445.
  11. Richards AM, Troughton RW. Use of natriuretic peptides to guide and monitor heart failure therapy. Clin Chem. 2012;58:62-71.
  12. Pfister R, Scholz M, Wielckens K, et al. The value of natriuretic peptides NT-pro-BNP and BNP for the assessment of left-ventricular volume and function. A prospective study of 150 patients.Dtsch Med Wochenschr. 2002;127:2605-2609.
  13. Siemens ADVIA Centaur® BNP directional insert; 2003.
  14. Redfield MM, Rodeheffer RJ, Jacobsen SJ, et al. Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol. 2002;40:976-982.
  15. Weber M, Hamm C. Role of B-type natriuretic peptid (BNP) and NT-proBNP in clinical routine.Heart. 2006;92:843-849.

SOURCE

B-type Natriuretic Peptide and proBNP, N-terminal

http://www.questdiagnostics.com/testcenter/testguide.action?dc=TS_BNP_proBNP

FIRST ARTICLE

Anemia as an Independent Predictor of Elevated N-terminal proBNP

Salman A. Haq, MD1, Mohammad E. Alam2, Larry Bernstein, MD, FCAP3,  LB Banko 1, Leonard Y. Lee, MD, FACS4, Barry I. Saul, MD, FACC5, Terrence J. Sacchi, MD, FACC6,  John F. Heitner, MD, FACC7
1Cardiology Fellow,  2  Clinical Chemistry Laboratories, 3 Program Director, Cardiothoracic Surgery, 4 Division of Cardiology,  Department of Medicine, New York Methodist Hospital-Weill Cornell, Brooklyn, NY

(Unpublished manuscript)  Poster Presentation:

Anemia as an Independent Predictor of Elevated N-Terminal proBNP Levels in
Patients without Evidence of Heart Failure and Normal Renal Function.

Haq SA, Alam ME, Bernstein L, Banko LB, Saul BI, Lee LY, Sacchi TJ, Heitner JF.

Table 1.  Patient Characteristics

Variable No Anemia(n=138) Anemia(n=80)
Median Age (years) 63 76
Men (%) 35 33
Creatinine (mg/dl) 0.96 1.04
Hemoglobin (g/dl) 13.7 10.2
LVEF (%) 67 63
Median NT-proBNP (pg/ml) 321.6 1896.0

Poster-ProBNP_final[1]

A series of slide showing the determination of the representation of normal NT-proBNP range
after removal of patient confounders.

Slide1

Slide10

Slide5

Slide8

ABSTRACT

Introduction

N-terminal proBNP (NT-proBNP) has emerged as a primary tool for diagnosing congestive heart failure (CHF). Studies have shown that the level of

  • NT-proBNP is affected by renal insufficiency (RI) and age, independent of the diagnosis of CHF.

There is some suggestion from recent studies that

  • anemia may also independently affect NT-proBNP levels.

Objective

To assess the affect of anemia on NT-proBNP independent of CHF, RI, and age.

Methods

We evaluated 746 consecutive patients presenting to the Emergency Department (ED) with shortness of breath and underwent evaluation with serum NT-proBNP.

All patients underwent a trans-thoracic echocardiogram (TTE) and clinical evaluation for CHF. Patients were included in this study if they had a normal TTE (normal systolic function, mitral inflow pattern and left ventricular (LV) wall thickness) and no evidence of CHF based on clinical evaluation. Patients were excluded if they had RI (creatinine > 2 mg/dl) or a diagnosis of sepsis. Anemia was defined using the World Health Organization (W.H.O.) definition of

  • hemoglobin (hgb) < 13 g/dl for males and hgb < 12 g/dl for females.

Results

Of the 746 consecutive patients, 218 patients (138 anemia, 80 no anemia) met the inclusion criteria. There was a markedly significant difference between

  • NT- proBNP levels based on the W.H.O. diagnosis of anemia.

Patients with anemia had a

  • mean NT- proBNP of 4,735 pg/ml compared to 1,230 pg/ml in patients without anemia (p=0.0001).

There was a markedly

  • significant difference in patients who had a hgb > 12 (median 295 pg/ml) when compared to
  • both patients with an hgb of 10.0 to 11.9 (median 2,102 pg/ml; p = 0.0001) and
  • those with a hgb < 10 (median 2,131 pg/ml; p = 0.001).

Linear regression analysis comparing hgb with log NT-proBNP was statistically significant (r = 0.395; p = 0.0001). MANOVA demonstrated that

  • elevated NT- proBNP levels in patients with anemia was independent of age.

Conclusion

This study shows that NT-proBNP is associated with anemia independent of CHF, renal insufficiency, sepsis or age.

INTRODUCTION

B-type natriuretic peptide (BNP) is secreted from the myocardium in response to myocyte stretch. 1-2 BNP is released from the myocytes as a 76 aminoacid N-terminal fragment (NT-proBNP) and a 32-amino acid active hormone (BNP). 3 These peptides have emerged as a primary non-invasive modality for the diagnosis of congestive heart failure (CHF). 4- 7 In addition, these peptides have demonstrated prognostic significance in patients with invasive modality for the diagnosis of

  • congestive heart failure (CHF). 4- 7
  • heart failure 8-9,
  • stable coronary artery disease 10, and
  • in patients with acute coronary syndromes. 11-14

Studies have shown that the level of NT- proBNP is affected by

  • age and renal insufficiency (RI) independent of the diagnosis of CHF. 15,16

There is some suggestion from the literature that

  • anemia may also independently affect NT-proBNP levels. 17-20

Willis et al. demonstrated in a cohort of 209 patients without heart failure that anemia was associated with an elevated NT- proBNP. 17 Similarly, in 217 patients undergoing cardiac catheterization, blood samples were drawn from the descending aorta prior to contrast ventriculography for BNP measurements and

  • anemia was found to be an independent predictor of plasma BNP levels. 18

The objective of this study is to assess the effect of anemia on NT-proBNP independent of CHF, sepsis, age or renal insufficiency.

METHODS

Patient population

The study population consisted of 746 consecutive patients presenting to the emergency room who underwent NT-proBNP evaluation for the evaluation of dyspnea. Transthoracic echocardiogram (TTE) was available on 595 patients. Patients were included in this study if they had a normal TTE, which was defined as normal systolic function (left ventricular ejection fraction [LVEF] > 45%), normal mitral inflow pattern and normal LV wall thickness. CHF was excluded based on thorough clinical evaluation by the emergency department attending and the attending medical physician. Patients with disease states that may affect the NT- proBNP levels were also excluded:

  1. left ventricular systolic dysfunction (LVEF < 45%),
  2. renal insufficiency defined as a creatinine > 2 mg/dl and
  3. sepsis (defined as positive blood cultures with two or more of the following systemic inflammatory response syndrome (SIRS) criteria: heart rate > 90 beats per minute;
  4. body temperature < 36 (96.8 °F) or > 38 °C (100.4 °F);
  5. hyperventilation (high respiratory rate) > 20 breaths per minute or, on blood gas, a PaCO2 less than 32 mm Hg;
  6. white blood cell count < 4000 cells/mm3 or > 12000 cells/mm³ (< 4 x 109 or > 12 x 109 cells/L), or greater than 10% band forms (immature white blood cells). 21

The study population was then divided into two groups, anemic and non- anemic. Anemia was defined using the world health organization (W.H.O.) definition of hemoglobin (hgb) < 13 g/dl for males and < 12 g/dl for females.The data was also analyzed by dividing the patients into three groups based on hgb levels i.e. hgb > 12, hgb 10 to 11.9 and hgb < 10.

Baseline patient data

Patient’s baseline data including age, gender, ethnicity, hemoglobin (hgb), hematocrit (hct), creatinine, NT- proBNP were recorded from the electronic medical record system in our institution. Chemistry results were performed on the Roche Modular System (Indianapolis, IN), with the NT- proBNP done by chemiluminescence assay. The hemogram was performed on the Beckman Coulter GenS. All TTE’s were performed on Sonos 5500 machine. TTE data collected included LVEF, mitral inflow pattern and LV wall thickness assessment.

Statistical analysis

The results are reported in the means with p < 0.05 as the measure of significance for difference between means. Independent Student’s t-tests were done comparing NT proBNP and anemia. Univariate ANOVAs and multivariate ANOVA (MANOVA) with post hoc tests using the Bonferroni method were used to compare NT- proBNP levels with varying ranges of hgb and age using SPSS 13.0 (SPSS, Chicago, IL). A linear regression analysis was performed using SYSTAT. Calculations included Wilks’Lamda, Pillai trace and Hotelling-Lawley trace. A GOLDMineR® plot was constructed to estimate the effects of age and anemia on NT- proBNP levels. The GOLDMineR® effects plot displays the odds-ratios for predicted NT-proBNP elevation versus the predictor values. Unlike the logistic regression, the ordinal regression, which the plot is derived from, can have polychotomous as well as dichotomous values, as is the case for NT-proBNP.

RESULTS

Of the 746 consecutive patients, 218 patients met the inclusion criteria (fig 1). Baseline characteristics of patients are listed in table 1. The median age for anemic patients was 76 years and 63 years for patients without anemia. One third of patients in both groups were men. The mean hemoglobin for

  • anemic patients was 10.2 g/dl as compared to 13.7 g/dl for non-anemic patients.
  • The mean LVEF of patients with anemia was 64% as compared to 67% for non-anemic patients.

Based on the WHO definition of anemia, 138 patients were determined to be anemic while 80 patients were diagnosed as non-anemic. There was a markedly  significant difference between NT-proBNP levels based on the WHO diagnosis of anemia.

Patients with anemia had a

  • mean NT-proBNP of 4,735 pg/ml compared to 1,230 pg/ml in patients without anemia (p = 0.0001).

Of the 218 patients in the study, 55 patients had a hgb of < 10 g/dl. Analysis using

  • hgb < 10 g/dl for anemia demonstrated a statistically significant difference in the NT-proBNP values.

Patients with a hgb < 10 g/dl had a mean NT- proBNP of 5,130 pg/ml

  • compared to 2,882 pg/ml in patients with a hgb of > 10 g/dl (p = 0.01)

The groups were also divided into three separate categories of hgb for subset analysis:

  • hgb > 12 g/dl,
  • hgb 10 to 11.9 g/dl and
  • hgb < 10 g/dl.

There was a markedly significant difference in

  •  the NT- ProBNP levels of patients who had a hgb > 12 g/dl (median 295 pg/ml) when
  • compared to those with a hgb range of 10.0 g/dl to 11.9 g/dl (median 2,102 pg/ml) (p = 0.0001),

and also a significant difference in

  • NT- proBNP levels of patients with a hgb > 12 g/dl (median 295 pg/ml) when
  • compared to a hgb of < 10 g/dl (median 2,131 pg/ml) (p = 0.001).

However, there was no statistically significant difference in NT-proBNP levels of patients with hgb 10 g/dl to 11.9 g/dl

  • when compared to those with a hgb of < 10 g/dl (p = 1.0).

A scatter plot comparing hgb with log NT-proBNP and fitting of a line to the data by ordinary least squares regression was significant (p = 0.0001) and demonstrated

  • a correlation between anemia and NT-proBNP levels (r = 0.395) (fig. 2).

MANOVA demonstrated that elevated NT- proBNP levels in patients with anemia was independent of age (Wilks’ Lambda [p = 0.0001]). In addition, using GOLDMineR® plots (figure 3a and 3b) with a combination of age and hb scaled as predictors of elevated NT-proBNP,

  • both age and hgb were required as independent predictors.

What about the effect of anemia? The GOLDminer analysis of ordinal regression was carried out in a database from which renal insufficiency and CHF were removed. The anemia would appear to have an independent effect on renal insufficiency. Figure 4 is a boxplot comparison of NT – proBNP, the age normalized function NKLog (NT- proBNP)/eGFR formed from taking 1000*Log(NT- proBNP) divided by the MDRD at eGFR exceeding 60 ml/min/m2 and exceeding 30 ml/min/m2. The transformed variable substantially makes the test independent of age and renal function. The boxplot shows the medians, 97.5, 75, 25 and 2.5 percentiles. There appears to be no significance in the NKLog(NT pro-BNP)/MDRD plot. Table II compares the NT-proBNP by WHO criteria at eGFR 45, 60 and 75 ml/mln/m2 using the t-test with unequal variance assumed, and the Kolmogorov-Smirnov test for nonparametric measures of significance. The significance at 60 ml/min/m2 is marginal and nonexistent at 75 ml/min/m2. This suggests that the contribution from renal function at above 60 ml/min2 can be ignored. This is consistent with the findings using the smaller, trimmed database, but there is an interaction between

  •  anemia, and
  •  eGFR at levels below 60 ml/min/m2

DISCUSSION

The findings in this study indicate that

  • anemia was associated with elevated NT-proBNP levels independent of CHF, renal insufficiency, sepsis or age.

These findings have been demonstrated with NT-proBNP in only one previous study. Wallis et al. demonstrated that after adjusting for age, sex, BMI, GFR, LVH and valvular disease;

  1. only age,
  2. valvular disease and
  3. low hemoglobin

were significantly associated with increased NT-proBNP. 18.

In our study, CHF was excluded based on both a normal TTE and a thorough clinical evaluation. In the only other study directly looking at NT- proBNP levels in anemic patients without heart failure

  • only 25% of patients had TTEs, with one patient having an LVEF of 40%. 17

BNP, the active molecule released after cleavage along with NT- proBNP, has also been studied in relation to blood hemoglobin levels. 18 In 263 patients undergoing cardiac catheterization  blood samples were drawn from the descending aorta prior to contrast ventriculography to determine the value of BNP. Anemia was present in 217 patients. Multivariate linear regression model adjusting for

  1.  age,
  2.  gender,
  3.  body mass index,
  4.  history of myocardial infarction,
  5.  estimated creatinine clearance, and
  6.  LVEF
  • found hgb to be an independent predictor of BNP levels.

In our study, patients with anemia were slightly older than those without anemia. However, both MANOVA and GOLDMineR® plot demonstrated that

  • elevated NT-proBNP levels in patients with anemia was independent of age.

Other studies have found that BNP is dependent on renal insufficiency and age. Raymond et al. randomly selected patients to complete questionnaires regarding CHF and

  1. then underwent pulse and blood pressure measurements,
  2.  electrocardiogram (ECG),
  3.  echocardiography and
  4.  blood sampling. 15

A total of 672 subjects were screened and 130 were determined to be normal, defined as

  • no CHF or ischemic heart disease,
  • normal LVEF,
  • no hypertension,
  • diabetes mellitus,
  • lung disease, and
  • not on any cardiovascular drugs.

They found

  1. older age,
  2. increasing dyspnea,
  3. high plasma creatinine and a
  4. LVEF < 45%

to be independently associated with an elevated NT-proBNP plasma level by multiple linear regression analysis. In another study, McCullough et al. evaluated the patients from the Breathing Not Properly Multinational Study

  • looking at the relationship between BNP and renal function in CHF. 16

Patients were excluded if they were on hemodialysis or had a estimated glomerular filteration rate (eGFR) of < 15 ml/min. They found that the BNP levels correlated significantly with the eGFR, especially in patients without CHF, suggesting

  1. chronic increased blood volume and
  2. increased left ventricular wall tension as a possible cause. 16

Our study was designed to exclude patients with known diseases such as CHF and renal insufficiency in order to demonstrate

  • the independent effect of anemia on elevated NT-proBNP levels.

The mechanism for elevated NT-proBNP levels in patients with anemia is unknown. Some possible mechanisms that have been reported in the literature include

  • hemodilution secondary to fluid retention in patients with CHF 18,
  • decreased oxygen carrying capacity with accompanying tissue hypoxia which
  • stimulates the cardio-renal compensatory mechanism leading to increased release of NT-proBNP. 17

The findings from our study suggest that

  •  NT-proBNP values should not be interpreted in isolation of hemoglobin levels and
  • should be integrated with other important clinical findings for the diagnosis of CHF.

Further studies are warranted

  1.  to assess the relationship between anemia and plasma natriuretic peptides, and
  2. possibly modify the NT-proBNP cutoff points for diagnosing acutely decompensated CHF in patients with anemia.

CONCLUSION

This study shows that elevated NT-proBNP levels are associated with anemia independent of

  •   CHF,
  •  renal insufficiency,
  •  sepsis and
  •  age.

NT-proBNP levels should be interpreted with caution in patients who have anemia.

 REFERENCES

1. Brunea BG, Piazza LA, de Bold AJ. BNP gene expression is specifically modulated by stretch and ET-1 in a new model of isolated rat atria.Am J Physiol  1997; 273:H2678-86.

2. Wiese S, Breyer T, Dragu A, et al. Gene expression of brain natriuretic peptide  in isolated atrial and ventricular human myocardium: influence of angiotensin II and diastolic fiber length. Circ 2000; 102:3074-79.

3. de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet 2003; 362:316-22.

4.   Dao Q, Krishnaswamy P, Kazanegra R, et al. Utility of B-type natriuretic  peptide in the diagnosis of congestive heart failure in an urgent care setting. J Am  Coll Cardiol 2001; 37:379-85.

5. Morrison LK, Harrison A, Krishnaswamy P, Kazanegra R, Clopton P, Maisel A. Utility of rapid natriuretic peptide assay in differentiating congestive heart failure from lung  disease in patients presenting with dyspnea.
J Am Coll Cardiol  2003; 39:202-09.

6.  Maisel AS, Krishnaswamy P, Nowak RM, et al.  Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002; 347:161-67.

7. Januzzi JL, Camargo CA, Anwaruddin S, et al. The N-terminal Pro-BNP investigation of dyspnea in the emergency department (PRIDE) study. Am J  Cardiol 2005; 95:948-954.

8.  Tsutamoto T, Wada A, Meada K, et al.   Attenuation of compensation of  endogenous cardiac natriuretic peptide system  in chronic heart failure: prognostic role  of plasma  brain natriuretic peptide concentration in patients with chronic  symptomatic  left ventricular dysfunction.
Circulation 1997; 96(2): 509-16.

9.  Anand IS, Fisher LD, Chiang YT, et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HEFT). Circulation 2003; 107:1278-1283.

10. Omland T, Richards AM, Wergeland R and Vik-Mo H. B-type natriuretic peptide and long term survival in patients with stable coronary artery disease.
Am J Cardiol 2005; 95:24-28.

11. Omland T, Aakvaag A, Bonarjee VV. et al. Plasma brain natriuretic peptide as an indicator of left ventricular systolic dysfunction and long term prognosis after acute myocardial infarction. Comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide.
Circulation 1996; 93:1963-1969.

12. de Lemos JA, Morrow DA, Bently JH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001; 345:1014-1021.

13. Richards AM, Nicholls MG, Espiner EA, et al. B-type natriuretic peptides and  ejection fraction for prognosis after myocardial infarction. Circulation 2003; 107:2786-2792.

14. Sabatine MS, Morrow DA, de Lemos JA, et al.  Multimarker approach to risk  stratification in non-ST elevation acute coronary syndromes: simultaneous  assessment of troponin I, C-reactive protein and B-type natriuretic peptide.
Circulation 2002; 105:1760-1763.

15. Raymond I, Groenning BA, Hildebrandt PR, Nilsson JC, Baumann M, Trawinski   J, Pedersen F.  The influence of age, sex andother variables on the plasma level of N-terminal pro brain natriureticpeptide in a large sample of the general  population. Heart 2003; 89:745-751.

16. McCollough PA, Duc P, Omland T, McCord J, Nowak RM, Hollander JE, et al. B-type natriuretic peptide and renal function in the diagnosis of heartfailure:  an analysis from the  Breathing Not Properly Multinational Study.
Am J Kidney Dis 2003; 41:571-579.

17. Willis MS, Lee ES, Grenache DG. Effect of anemia on plasma concentrations of  NT-proBNP.
Clinica Chim Acta 2005; 358:175-181.

18. Wold Knudsen C, Vik-Mo H, Omland T. Blood hemoglobin is an independent  predictor of B-type natriuretic peptide.
Clin Sci 2005; 109:69-74.

19. Tsuji H, Nishino N, Kimura Y, Yamada K, Nukui M, et al. Haemoglobin level influences plasma brain natriuretic peptide concentration. Acta Cardiol 2004;59:527-31.

20. Wu AH, Omland T, Wold KC, McCord J, Nowak RM, et al. Relationship  of B-type natriuretic peptide and anemia  in patients withand without heart failure:  A substudy from the Breathing Not Properly(BNP) Multinational Study.
Am J  Hematol 2005; 80:174-80.

22. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, et al.  Definitions for sepsis and organ failure and guidelines for theuse of innovative therapies in sepsis.  The ACCP/SCCM Consensus Conference Committee. Chest. 1992;101(6):1644-55.

Table Legends

Table I. Clinical characteristics of the study population

Table II. Comparison of NT- proBNP means under WHO criteria at different GFR

Table I
Variable No Anemia(n=80) Anemia(n=138)
Median age (years) 63 76
Gender
    Men (%) 27 (34) 47 (34)
    Women (%) 53 (66) 91 (66)
Weight (kg) 82.9 80.1
Chest Pain 21 (26) 3 (2)
Hemoglobin (g/dl) 13.7 10.2
Hematocrit (%) 40.5 30.5
Mean Corpuscular Volume 97 87
Creatinine (mg/dl) 0.99 1.07
Median NT-proBNP (pg/ml) 321 1896
Medical History
    HTN (%) 12 (15) 51 (37)
    Prior MI (%) 11 (14) 5 (4)
    ACS (%) 16 (20) 3 (2)
    CAD (%) 2 (1) 3 (2)
     DM (%) 18 (22) 11 (8)
Medication
   Clopidogrel 58 (72) 15 (11)
   Beta Blockers 68 (85) 27 (20)
   Ace Inhibitors 45 (56) 18 (13)
   Statins 57 (71) 17 (12)
   Calcium Channel Blocker 17 (21) 8 (6)
LVEF (%) 67 64

HTN: Hypertension CAD: Coronary Artery Disease
MI: Myocardial Infarction DM: Diabetes Mellitus
ACS: Acute Coronary Syndrome LVEF: Left Ventricular Ejection Fraction

Table II
GFR WHO Mean P (F) N NPar
> 45 0 3267 0.022 (4.33) 661
1 4681
> 60* 0 2593 0.031 (5.11) 456 0.018
1 4145
> 60r 0 786 0.203 (3.63) 303 0.08
1 3880
> 75 0 2773 > 0.80 320 0.043
1 3048

*AF, valve disease and elevated troponin T included
r AF, valve disease and elevated troponin T removed

FIGURE LEGENDS

FIGURE 1. Study population flow chart. (see poster)
FIGURE 2. Relationship between proBNP and hemoglobin. (see above)
FIGURE 3. NT-proBNP levels in relation to anemia (see above)

Supplementary Material

Table based on LatentGOLD Statistical Innovations, Inc., Belmont, MA., 2000: Jeroen Vermunt & Jay Magidson)

4-Cluster Model

Number of cases                                   408
Number of parameters (Npar)             24

Chi-squared Statistics
Degrees of freedom (df)                          71                     p-value
L-squared (L²)                                    80.2033                    0.21
X-squared                                            80.8313                     0.20
Cressie-Read                                        76.6761                     0.30
BIC (based on L²)                          -346.5966
AIC3 (based on L²)                        -132.7967
CAIC (based on L²)                       -417.5966

Model for Clusters
 Intercept                Cluster1      Cluster2     Cluster3     Cluster4     Wald     p-value
————–           0.1544           0.1434        0.0115        -0.3093     1.1981     0.75
Cluster Size           0.2870          0.2838       0.2487          0.1805
(across)

LogNTpr
< 1.5                       0.0843           0.2457       0.0006          0.0084
1.6-2.5                   0.6179            0.6458       0.0709          0.2809
2.5-3.5                  0.2848           0.1067         0.5319          0.5883
> 3.5                      0.0130           0.0018         0.3966         0.1224
MDRD
> 90                     0.1341             0.7919         0.0063         0.6106
61-90                  0.6019            0.2040          0.1633         0.3713
41-60                  0.2099            0.0041          0.3317         0.0175
< 41                     0.0542            0.0001         0.4987        0.0006
age
under 51           0.0668           0.5646          0.0568        0.0954
51-70                 0.3462            0.3602          0.3271         0.3880
over 70             0.5870            0.0752          0.6161         0.5166
WHO
No anemia      0.7518             0.6556          0.2041         0.0998
Anemia            0.2482             0.3444          0.7959         0.9002

———          Cluster1          Cluster2      Cluster3      Cluster4
Overall           0.2870            0.2838         0.2487        0.1805
(down)

LogNTpro
< 1.5                0.2492              0.7379           0.0013         0.0116
1.6-2.5            0.4163               0.4243           0.0427        0.1167
2.6-3.5           0.2296               0.0887          0.3723        0.3095
> 3.5              0.0328                0.0023          0.7982        0.1666
MDRD
> 90              0.1001                0.5998           0.0043        0.2958
61-90           0.5198                 0.1716           0.1136         0.1950
41-60           0.3860                 0.0055          0.5847         0.0238
< 41             0.1205                  0.0002          0.8785         0.0008
 age
< 51            0.0720                 0.7458           0.0910          0.0912
51-70         0.3036                 0.3084           0.2013          0.1867
over 70     0.3773                  0.0409          0.3633           0.2186
 WHO
No anemia 0.4589              0.3957           0.1076           0.0378
Anemia     0.1342                 0.1844            0.3742           0.3073

Hemoglobin on NT proBNP 3

SECOND ARTICLE

The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study

Donald S Silverberg, MDa; Dov Wexler, MDa; David Sheps, MDa; Miriam Blum, MDa; Gad Keren, MDa; Ron Baruch, MDa; Doron Schwartz, MDa; Tatyana Yachnin, MDa; Shoshana Steinbruch, RNa; Itzhak Shapira, MDa; Shlomo Laniado, MDa; Adrian Iaina, MDa

J Am Coll Cardiol. 2001;37(7):1775-1780. doi:10.1016/S0735-1097(01)01248-7

http://content.onlinejacc.org/article.aspx?articleid=1127229

OBJECTIVES

This is a randomized controlled study of anemic patients with severe congestive heart failure (CHF) to assess the effect of correction of the anemia on cardiac and renal function and hospitalization.

BACKGROUND

Although mild anemia occurs frequently in patients with CHF, there is very little information about the effect of correcting it with erythropoietin (EPO) and intravenous iron.

METHODS

Thirty-two patients with moderate to severe CHF (New York Heart Association [NYHA] class III to IV)
who had a left ventricular ejection fraction (LVEF) of 40% despite maximally tolerated doses of CHF medications and
  • whose hemoglobin (Hb) levels were persistently between 10.0 and 11.5 g% were randomized into two groups.
Group A (16 patients) received subcutaneous EPO and IV iron to increase the level of Hb to at least 12.5 g%. In Group B (16 patients) the anemia was not treated. The doses of all the CHF medications were maintained at the maximally tolerated levels except for oral and intravenous (IV) furosemide, whose doses were increased or decreased according to the clinical need.

RESULTS

Over a mean of 8.2 +/- 2.6 months,
  • four patients in Group B and none in Group A died of CHF-related illnesses.
  • The mean NYHA class improved by 42.1% in A and worsened by 11.4% in B.
  • The LVEF increased by 5.5% in A and decreased by 5.4% in B.
  • The serum creatinine did not change in A and increased by 28.6% in B.
  • The need for oral and IV furosemide decreased by 51.3% and 91.3% respectively in A and increased by 28.5% and 28.0% respectively in B.
  • The number of days spent in hospital compared with the same period of time before entering the study decreased by 79.0% in A and increased by 57.6% in B.

CONCLUSIONS

When anemia in CHF is treated with EPO and IV iron, a marked improvement in cardiac and patient function is seen,
  • associated with less hospitalization and renal impairment and less need for diuretics. (J Am Coll Cardiol 2001;37:1775– 80)

Anemia of any cause is known to be capable of causing congestive heart failure (CHF) (1). In patients hospitalized with CHF the 

  • mean hemoglobin (Hb) is about 12 g% (2,3),

which is considered the lower limit of normal in adults (4). Thus, anemia appears to be

common in CHF. Recently, in 142 patients in our special CHF outpatient clinic, we found that

  • as the CHF worsened, the mean Hb concentration decreased, from 13.7 g% in mild CHF (New York Heart Association [NYHA] class I) to 10.9 g% in severe CHF (NYHA 4), and
  • the prevalence of a Hb 12 g% increased from 9.1% in patients with NYHA 1 to 79.1% in those with NYHA 4 (5).
The Framingham Study has shown that anemia is an
  • independent risk factor for the production of CHF (6).
Despite this association of CHF with anemia,
  • its role is not mentioned in the 1999 U.S. guidelines for the diagnosis and treatment of CHF (7), and
  • many studies consider anemia to be only a rare contributing cause of hospitalization for CHF (8,9).
Recently, we performed a study in which the anemia of severe CHF that was resistant to maximally tolerated doses of standard medications
  • was corrected with a combination of subcutaneous (sc) erythropoietin (EPO) and intravenous iron (IV Fe) (5).
We have found this combination to be safe, effective and additive
  • in the correction of the anemia of chronic renal failure (CRF) in both
  • the predialysis period (10) and the dialysis period (11).
The IV Fe appears to be more effective than oral iron (12,13). In our previous study of CHF patients (5), the treatment resulted in
  • improved cardiac function,
  • improved NYHA functional class,
  • increased glomerular filtration rate,
  • a marked reduction in the need for diuretics and
  • a 92% reduction in the hospitalization rate
compared with a similar time period before the intervention. In the light of these positive results, a prospective randomized study was undertaken
  • to determine the effects of the correction of anemia in severe symptomatic CHF resistant to maximally tolerated CHF medication.

Abbreviations and Acronyms

CABG coronary artery bypass graft
CHF congestive heart failure
CRF chronic renal failure
EPO erythropoietin
%Fe Sat percent iron saturation
GFR glomerular filtration rate
Hb hemoglobin
Hct hematocrit
IU international units
IV intravenous
LVEF left ventricular ejection fraction
NYHA New York Heart Association
PA pulmonary artery
sc subcutaneous
SOLVD Studies Of Left Ventricular Dysfunction

MATERIALS AND METHODS

Patients.Thirty-two patients with CHF were studied. Before the study, the patients were treated for least six months in the CHF clinic with

  • maximally tolerated doses of angiotensin-converting enzyme inhibitors, the beta-blockers bisoprolol or carvedilol, aldospirone, long-acting nitrates, digoxin and oral and intravenous (IV) furosemide.

In some patients these agents could not be given because of contraindications and in others they had to be stopped because of side effects. Despite this maximal treatment

  • the patients still had severe CHF  (NYHA classIII), with  fatigue and/or shortness of breath  on even mild exertion or at rest.  All had levels of
  • Hb in the range of 10 to 11.5 g%  on at least three consecutive visits over a three-week period.
  • All had a LVEF of 40%.

Secondary causes of anemia including hypothyroidism, and folic acid and vitamin B12 deficiency were ruled out and

  • there was no clinical evidence of gastrointestinal bleeding.

The patients were randomized consecutively into two groups:

  • Group A, 16 patients, was treated with sc EPO and IV Fe to achieve a target Hb of at least 12.5 g%.
  • Group B, 16 patients, did not receive the EPO and IV Fe.

Treatment protocol for correction of anemia.

All patients in Group A received the combination of sc EPO and IV Fe. The EPO was given once a week at a starting dose of 4,000 international units (IU) per week  and
the dose was increased  to two  or  three  times a week or decreased to once every few weeks as  necessary

  • to achieve and maintain a target Hb of 12.5 g%.

The IV Fe (Venofer-Vifor International, Switzerland), a ferric sucrose product, was given in a dose of 200 mg IV in 150 ml saline over 60 min every two weeks

  • until the serum ferritin reached 400 g/l or
  • the %Fe saturation (%Fe Sat is serum iron/total iron binding capacity 100) reached 40% or
  • the Hb reached 12.5g%. 

The IV Fe was then given at longer intervals as needed to maintain these levels.

Investigations. 

Visits to the clinic were at two- to three week intervals depending on the patient’s status. This was the same frequency of visits to the CHF clinic as before then,

  • potassium and ferritin and %Fe Sat were performed on every visit.
  • blood pressure was measured by an electronic device on every visit.
  • LVEF was measured initially and at four- to six-month intervals by MUGA radioisotope ventriculography.

This technique measures

  • the amount of blood in the ventricle at the end of systole and at the end of diastole, thus giving
  • a very accurate assessment of the ejection fraction.

It has been shown to be an accurate and reproducible method of measuring the ejection fraction (14).  Hospital records were reviewed at the end of the intervention period to compare

  • the number of days hospitalized during the study with 
  • the number of days hospitalized during a similar period 
    • when the patients were treated in the CHF clinic before the initial randomization and entry into the study.

Clinic records were reviewed to evaluate the types and doses of CHF medications used before and during the study. The mean follow-up for patients was 8.2 +/-  2.7 months (range 5 to 12 months).  The study was done with the approval of the local ethics committee.Statistical analysis.

An analysis of variance with repeated measures (over time) was performed to compare the two study groups (control vs. treatment) and

  • to assess time trend and the interactions between the two factors.
  • A separate analysis was carried out for each of the outcome parameters.
  • The Mann-Whitney test was used to compare the change in NYHA class between two groups.

All the statistical analysis was performed by SPSS (version 10).

RESULTS

The mean age in Group A (EPO and Fe) was 75.3 +/-  14.6 years and in group B was 72.2 +/-  9.9 years. There were 11 and 12 men in Groups A and B, respectively.
Before the study the two groups were similar in
  1. cardiac function,
  2. comorbidities,
  3. laboratory investigations and
  4. medications
  • (Tables 1, 2 and 3), except for IV furosemide (Table 3),
which was higher in the treatment group. The mean NYHA class of Group A before the study was 3.8  0.4 and was 3.5  0.5 in Group B. The contributing factors to CHF in Groups A and B, respectively, are seen in Table 1 and were similar.
Table 1. Medical Conditions and Contributing Factors to Congestive Heart Failure in the 16 Patients Treated for the Anemia and in the 16 Controls

Table 1 medical conditions heart failure anemia

Table 2. The Effect of Correction of Anemia by Intravenous Iron and Erythropoietin Therapy on Various Parameters in 16 Patients in the Treatment (A) and 16 in the Control (B) Group

Table 2 medications to treat heart failure anemia

p values are given for analysis of variance with repeated measures and for independent t tests for comparison of baseline levels between the two groups.
BP  blood pressure; Fe Sat  iron saturation; Hb  hemoglobin; IV  intravenous; NS  not stated; Std Dev.  standard deviation.

The main contributing factors to CHF were considered to be

  • ischemic heart disease (IHD) in 11 and 10 patients respectively,
  • hypertension in two and two patients,
  • valvular heart disease in twoand two patients, and
  • idiopathic cardiomyopathy in one and two patients, respectively.

A significant change after treatment was observed in the two groups in the following parameters:

  • IV furosemide,
  • days in hospital,
  • Hb,
  • ejection fraction,
  • serum creatinine and
  • serum ferritin.
In addition, the interaction between the study group and time trend was significant in all measurements except for blood pressure and %Fe Sat. This interaction indicates that
  • the change over time was significantly different in the two groups.
Table 3. The Effect of Correction of Anemia by Intravenous Iron and Erythropoietin Therapy on Various Parameters in 16 Patients in the Treatment (A) and 16 in the Control (B) Group

Table 3  CHF aneia EPO

p values are given for analysis of variance with repeated measures and for independent t tests for comparison of baseline levels between the two groups.
BP  blood pressure; Fe Sat  iron saturation; Hb  hemoglobin; IV  intravenous; NS  not stated; Std Dev.  standard deviation.

We find in the comparisons of Tables 2 and 3:

  1. before treatment the level of oral furosemide was higher in the control group (136.2 mg/day) compared with the treatment group (132.2 mg/day).
  2. after treatment, while the dose of oral furosemide of the treated patients was reduced  to 64.4 mg/day
  • the dose of the nontreated patients was increased to 175 mg/day.

The same results of improvement in the treated group and deterioration in the control group are expressed in the following parameters:

  1. IV furosemide, days in hospital,
  2. Hb,
  3. ejection fraction and
  4. serum creatinine.

The NYHA class was

  • 3.8 +/- 0.4 before treatment and 2.2 +/- 0.7 after treatment in Group A  (delta mean = - 1.6) and
  • 3.5 +/-  0.7 before treatment and 3.9 +/- 0.3 after treatment in Group B. (delta mean = 0.4)

The improvement in NYHA class was significantly higher (p < 0.0001) in the treatment group compared with the control group (Table 4).

Table 4. Changes from Baseline to Final New York Heart Association (NYHA) Class
Initial minus final

Table 4  changes from NYHA baseline  CHF anemia

The improvement in NYHA class was statistically higher (p <  0.0001) in the treatment group compared with control.

There were no deaths in Group A and four deaths in Group B.

Case 1: A 71-year-old woman with severe mitral insufficiency and severe pulmonary hypertension  (a pulmonary artery [PA] pressure of 75 mm Hg) had persistent NYHA 4 CHF  and died during mitral valve surgery  seven months  after onset of the study. She was hospitalized for 21 days  in the seven months before randomization and for 28 days  during the seven months after randomization.

Case 2:

A 62-year-old man with a longstanding history of hypertension complicated by IHD, coronary artery bypass graft (CABG) and atrial fibrillation had persistent NYHA 4 CHF  and a PA pressure of 35 mm Hg,  and died from pneumonia and septic shock eight months after onset of the study. He was hospitalized for seven days in the eight months before randomization and for 21 days during the eight months  after
randomization.

Case 3:
A 74-year old man with IHD, CABG, chronic obstructive pulmonary disease, a history of heavy smoking and diabetes had persistent NYHA 4 CHF and a PA pressure of  28 mm Hg, and died of pulmonary  edema and cardiogenic shock nine months after onset of the study. He was hospitalized for 14 days in the nine months before  randomization and for 41 days during the nine months after randomization.

Case 4:
A 74-year-old man with a history of IHD, CABG, diabetes, dyslipidemia, hypertension and atrial fibrillation, had persistent NYHA 4 CHF and a PA pressure of 30 mm Hg,  and died of pneumonia and septic shock   six months after onset of the study. He was hospitalized for five days in the six months before randomization and for 16 days during the nine months after randomization.

DISCUSSION

 Main findings.

The main finding of the present study is that the correction of

  • even mild anemia in patients with symptoms of very severe CHF despite being on maximally tolerated drug therapy
  • resulted in a significant improvement in their cardiac function and NYHA functional class.

There  was also a large

  • reduction in the number of days of  hospitalization compared with a similar period before the  intervention.
  • all this was achieved despite a marked reduction in the dose of oral and IV furosemide.

In the group in whom the anemia was not treated, four  patients died during the study. In all four cases

  • the CHF was unremitting and contributed to the deaths. 

In addition,  for the group as a whole, 

  • the LVEF, the NYHA class and  the renal function worsened.

There was also need for

  • increased oral and IV furosemide as well as increased  hospitalization.

Study limitations.

The major limitations of this study are

  1. the smallness of the sample size and
  2. the fact that randomization and treatment were not done in a blinded fashion.

Nevertheless, the two groups were almost identical in

  1. cardiac, renal and anemia status;
  2. in the types and doses of medication they were taking before and during the intervention and
  3. in the number of hospitalization days before the intervention.

Although the results of this study, like those of  our previous uncontrolled study (5), suggest that

  • anemia may play an important role in the mortality and morbidity of  CHF,
  • a far larger double-blinded controlled study should be carried out to verify our findings.

Anemia as a risk factor for hospitalization and death in CHF.

Our results are consistent with a recent analysis of 91,316 patients hospitalized with CHF (15). Anemia was found to be a stronger predictor of

  • the need for early rehospitalization than  was hypertension,  IHD or the presence of a previous CABG.  

A recent analysis of the Studies Of Left Ventricular Dysfunction (SOLVD) (16) showed that

  • the level of hematocrit (Hct) was an independent risk factor for mortality.

During a mean follow-up of 33 months the mortality was

  • 22%, 27% and 34% for those with a Hct of 40, 35 to 40 and 35 respectively.

The striking response of our patients to

  • correction of mild anemia suggests that the failing heart may be very susceptible to anemia.

It has, in fact, been found in both animal (17) and human studies (17–19) that

  • the damaged heart is more vulnerable to anemia and/or ischemia than is the normal heart.

These stimuli may result in a more marked reduction in cardiac function than occurs in the normal heart and may explain why,  in our study,

  • the patients were so resistant to high doses of CHF medications and
  • responded so well when the anemia was treated.

Our findings about the importance of anemia in CHF are not surprising when one considers that, in dialysis patients,

  • anemia has been shown to be associated with an increased prevalence and incidence of CHF (20) and that
  • correction of anemia in these patients is associated with improved
    • cardiac function (21,22),
    • less mortality (23,24) and
    • fewer hospitalizations (23,25).

Effect of improvement of CHF on CRF.

Congestive heart failure can cause progressive renal failure (26,27). Renal ischemia is found very early on

  • in patients with cardiac dysfunction (28,29), and
  • chronic ischemia may cause progression of renal failure (30). Indeed, the development of
  • CHF in patients with essential hypertension has been found to be one of the most powerful predictors of
  • the eventual development of end-stage renal disease (31).

Patients who develop CHF after a myocardial infarction experience a

  • fall in the glomerular filtration rate (GFR) of about 1 ml/min/month if the CHF is not treated (32).

In another recent analysis of the SOLVD study, treating the CHF with

  • both angiotensin-converting enzyme inhibitors and beta-blockers resulted in better preservation of the renal function than did
  • angiotensin-converting enzyme inhibitors alone (26),
suggesting that the more aggressive the treatment of the CHF, the better the renal function is preserved. In the present study, as in our previous one (5), we found that the deterioration of GFR was prevented with
  • successful treatment of the CHF, including correction of the anemia, whereas
  • the renal function worsened when the CHF remained severe

All these findings suggest that early detection and treatment of CHF and systolic and/or diastolic dysfunction from whatever cause could prevent

  • the deterioration not only of the cardiac function
  • but of the renal function as well.

This finding has very broad implications in the prevention of CRFbecause most patients with advanced CRF have

  • either clinical evidence of CHF or at least some degree of systolic dysfunction (33).

Systolic and/or diastolic dysfunction can occur early on in many  conditions, such as

  • essential hypertension (34),
  • renal disease of any cause (35,36) or
  • IHD, especially after a myocardial infarction (37).

The early detection and adequate treatment of this cardiac dysfunction, including correction of the anemia, could prevent this cardiorenal insufficiency. To detect cardiac dysfunction early on, one would need  at least an echocardiogram and MUGA radio-nucleotide ventriculography. These tests should probably be done not only in patients with signs and symptoms of CHF,   but in all patients where CHF or systolic  and/or diastolic dysfunction are suspected, such as those with a history of heart disease or suggestive changes of ischemia or hypertrophy on the electrocardiogram, or in patients with hypertension or renal disease.

Other positive cardiovascular effects of EPO treatment.

Another possible explanation for the improved cardiac function in this study may be the direct effect that EPO itself has on improving cardiac muscle function (38,39) and myocardial cell growth (39,40) unrelated to its  effect of the anemia. In fact EPO may be  crucial in the formation of the heart muscle in utero (40). It may also improve  endothelial function (41).  Erythropoietin may be superior to blood transfusions  not only  because adverse reactions to EPO are infrequent, but also because

  • EPO causes the production and release of young cells from the bone marrow into the blood.

These cells have an oxygen dissociation curve that is shifted to the right of the normal curve, causing the release of

  • much greater amounts of oxygen into the tissues than occurs normally (42).

On the other hand, transfused blood consists of older red cells with an oxygen dissociation curve that is

  • shifted to the left, causing the release of much less oxygen into the tissues than occurs normally (42).

The combination of IV Fe and EPO. The use of IV Fe along with EPO has been found to have an additive effect, 

  • increasing the Hb even more than would occur with EPO alone while at the same time
  • allowing the dose of EPO to be reduced (10 –13).
  • The lower dose of EPO will be cost-saving and also reduce the chances of hypertension developing (43).
 We used iron sucrose (Venofer) as our IV Fe medication because, in our experience, it is extremely well tolerated (10,11) and  
  • has not been  associated  with any serious side effects in more than 1,200 patients over six years.

Implications of treatment of anemia in CHF. The correction of anemia is not a substitute for the well-documented effective therapy of CHF but seems to be  an important, if not vital,  addition to the therapy. It is surprising, therefore,  that judging from  the  literature  on CHF,

  • such an obvious treatment for improving CHF is so rarely considered.

We believe that correction of the anemia will have an important role to play in

  • the amelioration of cardiorenal insufficiency, and that this improvement will have
  • significant economic  implications as well.

Acknowledgments

The authors thank Rina Issaky, Miriam Epstein, Hava Ehrenfeld and Hava Rapaport for their secretarial assistance.
Reprint requests and correspondence: Dr. D. S. Silverberg, Department of Nephrology, Tel Aviv Medical Center, Weizman 6, Tel Aviv, 64239, Israel.

 THIRD ARTICLE

The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations

Donald S Silverberg, MDa; Dov Wexler, MDa; Miriam Blum, MDa; Gad Keren, MDa; David Sheps, MDa; Eyal Leibovitch, MDa; David Brosh, MDa; Shlomo Laniado, MDa; Doron Schwartz, MDa; Tatyana Yachnin, MDa; Itzhak Shapira, MDa; Dov Gavish, MDa; Ron Baruch, MDa; Bella Koifman, MDa; Carl Kaplan, MDa; Shoshana Steinbruch, RNa; Adrian Iaina, MDa

J Am Coll Cardiol. 2000;35(7):1737-1744. doi:10.1016/S0735-1097(00)00613-6

http://content.onlinejacc.org/article.aspx?articleid=1126474

OBJECTIVES

This study evaluated the prevalence and severity of anemia in patients with congestive heart failure (CHF) and

  • the effect of its correction on cardiac and renal function and hospitalization.

BACKGROUND

The prevalence and significance of mild anemia in patients with CHF is uncertain, and the role of erythropoietin with intravenous iron supplementation in treating this anemia is unknown.

METHODS

In a retrospective study, the records of the 142 patients in our CHF clinic were reviewed to find
  • the prevalence and severity of anemia (hemoglobin [Hb]12 g).
In an intervention study, 26 of these patients, despite maximally tolerated therapy of CHF for at least six months, still had had severe CHF and were also anemic. They were treated with
  • subcutaneous erythropoietin and intravenous iron sufficient to increase the Hb to 12 g%.
The doses of the CHF medications, except for diuretics, were not changed during the intervention period.

RESULTS

The prevalence of anemia in the 142 patients increased with the severity of CHF,
  • reaching 79.1% in those with New York Heart Association class IV.
In the intervention study, the anemia of the 26 patients was treated for a mean of 7.2 5.5 months.
  • The mean Hb level and mean left ventricular ejection fraction increased significantly.
  • The mean number of hospitalizations fell by 91.9% compared with a similar period before the study.
  • The New York Heart Association class fell significantly,
  • as did the doses of oral and intravenous furosemide.
  • The rate of fall of the glomerular filtration rate slowed with the treatment.

CONCLUSIONS

Anemia is very common in CHF and its successful treatment is associated with a significant improvement in
  • cardiac function,
  • functional class,
  • renal function and
  • in a marked fall in the need for diuretics and hospitalization.
Abbreviations and Acronyms
ACE Angiotensin-converting enzyme
CHF congestive heart failure
COPD chronic obstructive pulmonary disease
CRF chronic renal failure
CVA cerebrovascular accident
EPO erythropoietin
Fe iron
g% grams Hb /100 ml blood
GFR glomerular filtration rate
Hb hemoglobin
Hct hematocrit
IV intravenous
LVEF left ventricular ejection fraction
LVH left ventriculr hypertrophy
NYHA New York Heart Association
%Fe Sat percent iron saturation
sc subcutaneous
TNF tumor becrosis factor
ACE Angiotensin-converting enzyme
CHF congestive heart failure
COPD chronic obstructive pulmonary disease
CRF chronic renal failure
CVA cerebrovascular accident
EPO erythropoietin
Fe iron
g% grams Hb /100 ml blood
GFR glomerular filtration rate
Hb hemoglobin
Hct hematocrit
IV intravenous
LVEF left ventricular ejection fraction
LVH left ventriculr hypertrophy
NYHA New York Heart Association
%Fe Sat percent iron saturation
sc subcutaneous
TNF tumor becrosis factor

The mean hemoglobin (Hb) in patients with congestive heart failure (CHF) is about 12 g Hb per 100 ml blood (g%) (1–3), which is considered to be the lower limit of normal in adult men and postmenopausal women (4). Thus, many patients with CHF are anemic, and

  • this anemia has been shown to worsen as the severity of the CHF progresses (5,6).
Severe anemia of any cause can produce CHF, and treatment of the anemia can improve it (7). In patients with chronic renal failure (CRF) who are anemic,
  • treatment of the anemia with erythropoietin (EPO) has improved many of the abnormalities seen in CHF,
  • reducing left ventricular hypertrophy (LVH) (8 –10),
  • preventing left ventricular dilation (11) and,
    • in those with reduced cardiac function, increasing the left ventricular ejection fraction (LVEF)(8 –10),
    • the stroke volume (12) and
    • the cardiac output (12).
In view of the high prevalence of anemia in CHF, it is surprising that we could find no studies in which EPO was used in the treatment of the anemia of CHF, and the use of EPO is not included in U.S. Public Health Service guide-lines of treatment of the anemia of CHF (13). In fact, anemia has been considered
  • only a rare contributing factor to the worsening of CHF, estimated as contributing to
  • no more than 0% to 1.5% of all cases (14 –16).
Perhaps for this reason, recent guidelines for the prevention and treatment of CHF do not mention treatment of anemia at all (17). If successful treatment of anemia could improve cardiac function and patient function in CHF,
  • this would have profound implications, because,
  • despite all the advances made in the treatment of CHF, it is still a major and steadily increasing cause of hospitalizations, morbidity and mortality (18 –20).
The purpose of this study is to examine
  • the prevalence of anemia (Hb 12 g%) in patients with different levels of severity of CHF and
  • to assess the effect of correction of this anemia in severe CHF patients
  • resistant to maximally tolerated doses of CHF medication.
A combination of subcutaneous (SC) EPO and intravenous (IV) iron (Fe) was used. We have found this combination to be additive in improving the anemia of CRF (21,22).

METHODS 

Patients.

The medical records of the 142 CHF patients being treated in our special outpatient clinic devoted to CHF were reviewed to determine the prevalence and severity of anemia and CRF in these patients. These patients were referred to the clinic either from general practice or from the various wards in the hospital.

Intervention study.

Despite at least six months of treatment in the CHF clinic,
  • 26 of the above patients had persistent, severe CHF (New York Heart Association [NYHA] class III),
  • had a Hb level of 12 g% and were on
    • angiotensin-converting enzyme [ACE] inhibitors, the 
    • alpha-beta-blocker carvedilol,
    • long-acting nitrates,
    • digoxin, 
    • aldactone and
    • oral and IV furosemide.

These 26 patients participated in an intervention study. The mean age was 71.76  8.12 years. There were 21 men and 5 women. They  all had a

  • LVEF below 35%,
  • persistent fatigue and
  • shortness

    of breath on mild to moderate exertion and often at rest, and had

  • required hospitalizations at least once during their follow-up in the CHF clinic for pulmonary edema.
In 18 of the 26 patients, the CHF was associated with ischemic heart disease either
  • alone in four patients, or
  • with hypertension in six,
  • diabetes in four,
  • the two together in three, or with
  • valvular heart disease in one.
Of the remaining eight patients,
  • four had valvular heart disease alone and
  • four had essential hypertension alone.
Secondary causes of anemia including
  • gastrointestinal blood loss (as assessed by history and by three negative stool occult blood examinations),
  • folic acid and vitamin B12 deficiency and
  • hypothyroidism were ruled out.
Routine gastrointestinal endoscopy was not carried out. The study passed an ethics committee.
Table 1. Initial Characteristics of the 142 Patients With CHF Seen in the CHF Clinic
Age, yearsMale/female,  %Associated conditionsDiabetesHypertensionDyslipidemiaSmoking

Main cardiac diagnosis
Ischemic heart disease

Dilated CMP

Valvular heart disease

Hypertension

LVEF,  %

Left atrial area (n 15 cm2)

Pulmonary artery pressure  (15 mm Hg)

Previous hospitalizations/year

Serum Na, mEq/liter

Serum creatinine, mg%

Hemoglobin, g%

70.1 +/- 11.1

79/21

28%

64%

72%

40%

74%

15%

6%

5%

32.5 +/- 12.2

31.3  +/- 10.3

43.1  +/-14.9

3.2  +/- 1.5

139.8  +/- 4.0

1.6   +/-  1.1

11.9   +/- 1.5

CMP  cardiomyopathy; LVEF  left ventricular ejection fraction; NYHA  New York Heart Association class.

Correction of the anemia.

All patients received the combination of SC EPO and IV Fe. The EPO was given once a week at a starting dose of 2,000 IU per week subcutaneously, and the dose was increased or decreased as necessary to achieve and maintain a target Hb of 12 g%. The IV Fe (Venofer-Vifor International, St. Gallen, Switzerland), a ferric sucrose product, was given in a dose of 200 mg IV in 150 ml saline over 60 min every week until the serum ferritin reached 400  g/liter or the percent Fe saturation (%Fe Sat: serum iron/total iron binding capacity   100) reached 40% or until the Hb reached 12 g%. The IV Fe was then given at longer intervals as needed to maintain these levels.

Medication dose.

Except for oral and IV furosemide therapy, the doses of all the other CHF medications, which were used in the maximum tolerated doses before the intervention, were kept unchanged during the intervention period.

Duration of the study.

The study lasted for a mean of 7.2  5.5 months (range four to 15 months).

Investigations.

Visits were at weekly intervals initially and then at two- to three-week intervals depending on the patient’s status. This was the same frequency of visits to the CHF clinic as before the intervention study.
  • A complete blood count, serum creatinine, serum ferritin and % Fe Sat were performed on every visit.
  •  An electronic device measured the blood pressure on every visit.
  • The LVEF was measured by a multiple gated ventricular angiography heart scan initially and at four- to six-month intervals.
Hospital records were reviewed to compare the number of hospitalizations during the time the patients were treated for the anemia with the number of hospitalizations
  • during a similar period of time that they were treated in the CHF clinic 
    before the anemia was treated.
Clinic records were reviewed to evaluate the types and doses of CHF medications used 
before and during the study.

Period of time that they were treated in the CHF clinic before the anemia was treated.

Clinic records were reviewed to evaluate the types and doses of CHF medications used before and during the study.  The glomerular filtration rate (GFR) was calculated from the serum creatinine by the formula: 1/serum creatinine in mg% x 100 GFR in ml/min. The rate of change of the GFR before and during the intervention period was calculated by comparing the change in GFR per month in the year before the intervention with that during the intervention.

Statistical analysis.

Mean standard deviation was calculated. One-way analysis of variance (ANOVA) was performed to compare parameter levels between the four NYHA groups. Hochberg’s method of multiple comparisons (23) was used for pair-wise comparison between two groups. A p value of less than 0.05 was considered statistically significant. In the intervention study, the significance  of the difference between the initial values and those at the end of the study for the individual parameters in the 26 treated patients was assessed by paired student’s t test; p < 0.05 was considered statistically significant. All the statistical analysis was performed by the SPSS program (Version 9, Chicago, Illinois).

 RESULTS

CHF: the whole study group.

The clinical, biochemical and hematological characteristics of the 142 patients seen in the clinic are shown in Tables 1 and 2.

  • Sixty-seven patients (47%) had severe CHF as judged by a NYHA class of IV (Table 2).
  • Seventy- nine of the 142 patients (55.6%) were anemic (Hb  12 g%).

The mean Hb level fell progressively from 13.73 +/- 0.83 g% in class I NYHA to 10.90 +/- 1.70 g% in class IV NYHA (p  0.01). The percentage of patients with Hb  12 g% increased from 9.1% in class I to 79.1% in class IV.
Fifty eight patients (40.8%) had CRF as defined as a serum creatinine  1.5 mg%. The mean serum creatinine increased from 1.18 +/_  0.38 mg% in class I NYHA, to 2.0 +/-    1.89 mg% in class IV NYHA, p  0.001. The percentage of patients with an elevated serum creatinine ( 1.5 mg%)      increased from 18.2% in class I to 58.2% in class IV.

The mean ejection fraction fell from 37.67 +/-  15.74% in class I to 27.72 +/-  9.68% (p  0.005) in class IV.

Table 2. LVEF and Biochemical and Hematological Parameters by NYHA Class in 142 Patients With CHF 
NYHA Class I II III IV  Significantly Different Pairs*

 *p  0.05 at least between the two groups by pair-wise comparison between groups.

†p  0.05 at least between the groups by ANOVA.

No. of patients

11

26  

38

67

(total 142) (%)

    (7.7)    (18.3)    (26.8)    (47.2)

Hb, g%†

13.73 (0.83)

13.38 (1.26)

11.95 (1.48)

10.90 (1.70) 

1–3, 1–4, 2–3, 2–4

Serum creatinine,

1.18

1.22

1.32

2.00

1–2, 1–3, 1–4

mg%†

    (0.38)     (0.29)      (0.38)     (1.89)

LVEF, %†

37.67 (15.74)

32.88 (12.41)

32.02 (10.99)

27.72 (9.68)

1–4, 2–4

Hb 12 g%,  (%)

1
(9.1)

5 (19.2) 

20 (52.6) 

53 (79.1)

Serum creatinine

    2      5     12     39

1.5 mg%,  (%) 

 (18.2)

(19.2)

(31.6)

 (58.2)

The intervention study: medications.

The percentage of patients receiving each CHF medication before and after the intervention period and the reasons for not receiving  them are seen in Table 3.

Table 3. Number (%) of the 26 Patients Taking Each Type of Medication Before and During the Intervention Period and the Reason Why the Medication Was Not Used

Medication    No. of Patients  (%)         Reason for Not Receiving the Medications (No. of Patients)
BP  blood pressure; CRF  chronic renal failure; IV  intravenous.

The main reason for not receiving:

  • 1) ACE inhibitors was the presence of reduced renal function;
  • 2) carvedilol was the presence of chronic obstructive pulmonary disease (COPD);
  • 3) nitrates was low blood pressure and aortic stenosis and
  • 4) aldactone was hyperkalemia.
Table 4. Mean Dose of Each Medication Initially and at the End of the Intervention Period in the 26 Patients

                                       No. of Patients                                 Initial Dose ^                 Final Dose^
Carvedilol (mg/day)                      20                                                        26.9 15.5                                   28.8 14.5
Captopril (mg/day)                          7                                                        69.6 40.0                                 70.7 40.4
Enalapril (mg/day)                        13                                                        25.7 12.5                                   26.9 12.6
Digoxin (mg/day)                          25                                                       0.10 0.07                                    0.10 0.07
Aldactone (mg/day)                       19                                                        61.2 49.2                                   59.9 47.1
Long-acting nitrates                      23                                                        53.2 13.2                                   54.1 14.4
Oral furosemide (mg/day)           26                                                      200.9 120.4                                78.3 41.3*
IV furosemide (mg/month)         26                                                      164.7 178.9                                  19.8 47.0*
*p  0.05 at least vs. before by paired Student’s t test.
^  +/-

The mean doses of the medications are shown in Table 4. 

The mean dose of oral furosemide was 200.9 +/-  120.4 mg/day before and 78.3 +/-  41.3 mg/day after the intervention (p   0.05). The dose of IV furosemide was 164.7 +/-  19.8,  178.9 mg/month before and  7.0 mg/month after the intervention (p  0.05).  

The doses of the other CHF medications were almost identical in the two periods.

Clinical results.

DEATHS.
There were three deaths during the intervention period. An 83-year-old man died after eight months of respiratory failure after many years of COPD, a 65-year-old man at eight months of a CVA with subsequent pneumonia and septic shock and a 70-year-old man at four months of septicemia related to an empyema that developed after aortic valve replacement.
HEMODIALYSIS.
Three patients, a 76-year-old man, an 85-year-old woman and a 72-year-old man, required chronic hemodialysis after six, 16 and 18 months, respectively. The serum creatinines of these three patients at onset of the anemia treatment were 4.2, 3.5 and 3.6 mg%, respectively. All three had improvement in their NYHA status but
  • their uremia worsened as the renal function deteriorated, demanding the initiation of dialysis.

In no cases, however, was pulmonary congestion an indication for starting dialysis.

Functional results (Table 5).

During the treatment period, the NYHA class fell from a mean of 3.66 +/- 0.47 to 2.66 +/- 0.70 (p 0.05), and
  • 24 had some improvement in their functional class.
The mean LVEF increased from 27.7 +/- 4.8 to 35.4  +/- 7.6% (p 0.001), an increase of  27.8%.
Compared with a similar period of time before the onset of the anemia treatment, the mean number of hospitalizations fell from 2.72 +/-  1.21 to 0.22 +/-  0.65 per patient (p   0.05)a decrease of 91.9%.
No significant changes were found in the mean systolic/diastolic blood pressure.

Hematological results (Table 5).

  • The mean hematocrit (Hct) increased from 30.14 +/- 3.12%) to 35.9  +/- 4.22% (p < 0.001).
  • The mean Hb increased from 10.16 +/- 0.95 g%) to 12.10 +/-  1.21 g% (p <  0.001).
  • The mean serum ferritin increased from 177.07 +/-  113.80  g/liter to 346.73 +/- 207.40 g/liter (p  0.005).
  • The mean serum Fe increased from 60.4 +/- 19.0 g% to 74 +/- .80  20.7 g% (p  0.005). 
  • The mean %Fe Sat increased from 20.05   6.04% to 26.14 =/- 5.23% (p  0.005).
  • The mean dose of EPO used throughout the treatment period was 5,227  +/- 455 IU per week, and
  • the mean dose of IV Fe used was 185.1 +/- 57.1 mg per month.
In four of the patients, the target Hb of 12 g% was maintained despite stopping the EPO for at least four months.

Renal results (Table 5).

The changes in serum creatinine were not significant. The estimated creatinine clearance fell at a rate of 0.95 + 1.31 ml/min/month before the onset of treatment of the anemia and increased at a rate of 0.85 + 2.77 ml/min/month during the treatment period.
Table 5. The Hematological and Clinical Data of the 26 CHF Patients at Onset and at the End of the Intervention Period

————–                                         Initial ^                                    Final^
Hematocrit, vol%                              30.14 3.12                            35.90 4.22*
Hemoglobin, g%                                10.16 0.95                              2.10 1.21*
Serum ferritin, g/liter                    177.07 113.80                       346.73  207.40*
Serum iron, g%                                  60.4 19.0                               74.8  20.7*
% iron saturation                              20.5 6.04                               26.14 5.23*
Serum creatinine, mg%                   2.59 0.77                                 2.73 1.55
LVEF, %                                              27.7 4.8                                   35.4  7.6*
No. hospitalizations/patient          2.72 1.21                                 0.22   0.65*
Systolic BP, mm Hg                       127.1 19.4                                128.9  26.4
Diastolic BP, mm Hg                       73.9 9.9                                   74.0   12.7
NYHA (0–4)                                     3.66 0.47                                2.66 0.70*
*p  0.05 at least vs before by paired Student’s t test.     ^ +/-
BP  blood pressure; LVEF  left ventricular ejection fraction; NYHA  New York Heart Association.

DISCUSSION

The main findings in the present study are that anemia is common in CHF patients and becomes progressively more prevalent and severe as CHF progresses. In addition, for patients with resistant CHF, the treatment of the associated anemia causes a marked improvement in their

  1. functional status,
  2. ejection fraction and
  3. GFR.
        • All these changes were associated with a markedly
            • reduced need for hospitalization and
            • for oral and IV furosemide.

The effect of anemia on the ischemic myocardium.

We used the IV Fe together with EPO to avoid the Fe deficiency caused by the use of EPO alone (38,39).
The Fe deficiency will cause

  • a resistance to EPO therapy and
  • increase the need for higher and higher doses to maintain the Hb level (39,40).

These high doses will not only be expensive but may increase the blood pressure excessively (41). The IV Fe reduces the dose of EPO needed to correct the anemia, because

  • the combination of SC EPO and IV Fe has been shown to have an additive effect on correction of the anemia of CRF (21,22,39,42).

Oral Fe, however, has no such additive effect (39,42). The relatively low dose of EPO needed to control the anemia in our study may explain why

  • the blood pressure did not increase significantly in any patient.

We used Venofer, an Fe sucrose product, as our IV Fe supplement because, in our experience (21,22,43), it has very few side effects and, indeed, no side effects with its use were encountered in this study.

The Effect of Anemia Correction on Renal Function.

Congestive heart failure is often associated with some degree of CRF (1–3,27–29), and

  • this is most likely due to renal vasoconstriction and ischemia (28,29).

When the anemia is treated and the cardiac function improves,

  • an increase in renal blood flow and glomerular filtration is seen (7,28).

In the present study, renal function decreased as the CHF functional class worsened (Table 2). The rate of deterioration of renal function was slower during the intervention period. Treatment of anemia in CRF has been associated with

  • a rate of progression of the CRF that is either unchanged (30) or is slowed (31–33).

It is possible, therefore, that adequate treatment of the anemia in CHF may, in the long term, help slow down the progression of CRF.

Possible Adverse Effects of Correction of the Anemia.

There has been concern, in view of the recent Amgen study (34), that correction of the Hct to a mean 42% in hemodialysis patients might increase cardiovascular events in those receiving EPO compared with those maintained at a Hct of 30%. Although there is much uncertainty about how to interpret this study (35), there is a substantial body of evidence that shows

  • correction of the anemia up to a Hb of 12 g% (Hct 36%) in CRF on dialysis is safe and desirable (35–38), and
  • results in a reduction in mortality, morbidity and in the number and length of hospitalizations.

The same likely holds true for the anemia of CHF with or without associated CRF. Certainly, our patients’ symptoms were strikingly improved, as was their cardiac function (LVEF) and need for hospitalization and diuretics. It remains to be established

  • if correction of the anemia up to a normal Hb level of 14 g% might be necessary in order to further improve the patient’s clinical state.

The Role of Fe Deficiency and its Treatment in the Anemia of CHF.

We used the IV Fe together with EPO to avoid the Fe deficiency caused by the use of EPO alone (38,39). The Fe deficiency will cause

  • a resistance to EPO therapy and increase the need for higher and higher doses to maintain the Hb level (39,40).

These high doses will not only be expensive but may

  • increase the blood pressure excessively (41).

The IV Fe reduces the dose of EPO needed to correct the anemia, because the combination of SC EPO and IV Fe has been shown to have an additive effect on correction of the anemia of CRF (21,22,39,42). Oral Fe,  however, has no such additive effect (39,42). The relatively low dose of EPO needed to control the anemia in our study may explain

  • why the blood pressure did not increase significantly in any patient.

We used Venofer, an Fe sucrose product, as our IV Fe supplement because, in our experience (21,22,43), it has very few side effects and, indeed, no side effects with its use were encountered in this study.

Read Full Post »


The Young Surgeon and The Retired Pathologist: On Science, Medicine and HealthCare Policy – The Best Writers Among the WRITERS

Curator: Aviva Lev-Ari, PhD, RN

Since January 2005, I am a Reader, Curator and Author of scientific articles in Life Sciences and Medicine.

On 12/11/2013, the Open access Scientific Journal launched on 4/2012, http://pharmaceuticalintelligence.com – has the following Site statistics:

Scientific Journal Site Statistics

Date

Views to Date

# of articles

NIH Clicks

Nature Clicks

6/24/2013

199,857

1,034

1,275

661

 7/29/2013  217,356  1,138  1,389  705
12/11/2013  293,694  1,464  1,693  828

By 12/10/2013, I have curated 783 articles, the list of titles is on 40 pages on http://pharmaceuticalintelligence.com.

Links to each article to be found at

http://pharmaceuticalintelligence.com/?s=Aviva+Lev-Ari%2C+PhD%2C+RN

Frontiers in Cardiology – 247 articles

http://pharmaceuticalintelligence.com/?s=Frontiers+in+Cardiology

These articles have been viewed, since the first article was published on 4/30/2012, by +90,000 viewers.

Author Views since 4/30/2012
2012pharmaceutical 93,106

Of all the readings and reviews I completed to date, my appreciation got bonded to two Science and Medicine writers:

and

I am inviting the e-Readers to join me on a language immersion during a LITERARY TOUR in Science, Medicine and HealthCare Policy. 

Part One: The Young Surgeon

Eric J. Topol, MD: Editor’s Note on The Young Surgeon

Atul Gawande, MD, MPH, wears many hats, including that of a surgeon, researcher, journalist, and author. In this segment of Medscape One-on-One, Dr. Gawande talks with Eric J. Topol, MD, about what inspires him, his plans for the future, and why he’s secretly a frustrated rock singer.

WATCH the INTERVIEW of December 06, 2013 on VIDEO

Eric Topol on Medscape > Medscape One-on-One

Atul Gawande on the Secrets of a Puzzle-Filled Career

, Atul Gawande, MD, MPH

http://www.medscape.com/viewarticle/815241?nlid=41903_2105&src=wnl_edit_medp_card&uac=93761AJ&spon=2

Atul Gawande is a surgeon, writer, and public health researcher. He practices general and endocrine surgery at Brigham and Women’s Hospital in Boston, and is Director of Ariadne Labs, a joint center for health systems innovation. He is Professor in the Department of Health Policy and Management at the Harvard School of Public Health and Professor of Surgery at Harvard Medical School. And he is also co-founder and chairman of Lifebox, an international not-for-profit implementing systems and technologies to reduce surgical deaths globally.

He has been a staff writer for the New Yorker magazine since 1998. He has written three bestselling books: Complications, which was a finalist for the National Book Award in 2002; Better, which was selected as one of the ten best books of 2007 by Amazon.com; and The Checklist Manifesto. He has won two National Magazine Awards, AcademyHealth’s Impact Award for highest research impact on health care, a MacArthur Fellowship, and he has been named one of the world’s hundred most influential thinkers by Foreign Policy and TIME.

ADDITIONAL LINKS

http://gawande.com/about

RESEARCH by Dr. Atul Gawande

Tsai TC, Joynt KE, Orav EJ, Gawande AA, Jha AK. Variation in Surgical-Readmission Rates and Quality of Hospital CareNew England Journal of Medicine Published online September, 2013.

Funk LM, Conley DM, Berry WR, Gawande AA. Hospital Management Practices and Availability of Surgery in Sub-Saharan Africa: A Pilot Study of Three HospitalsWorld Journal of Surgery Published online August, 2013.

Nehs MA, Ruan DT, Gawande AA, Moore FD Jr, Cho NL.Bilateral neck exploration decreases operative time compared to minimally invasive parathyroidectomy in patients with discordant imagingWorld Journal of SurgeryPublished online July, 2013.

Joynt KE, Gawande AA, Orav EJ, Jha AK.Contribution of Preventable Acute Care Spending to Total Spending for High-Cost Medicare PatientsJAMA Published online June 24, 2013.

McCrum ML, Joynt KE, Orav EJ, Gawande AA, Jha AK.Mortality for Publicly Reported Conditions and Overall Hospital Mortality RatesJAMA Published online June 24, 2013.

Spector JM, Lashoher A, Agrawal P, Lemer C, Dziekan G, Bahl R, Mathai M, Merialdi M, Berry W, and Gawande AA.Designing the WHO Safe Childbirth Checklist Program to Improve Quality of Care at ChildbirthInternational Journal of Gynecology & Obstetrics Published online June 5, 2013.

Barnet CS, Arriaga AF, Hepner DL, Correll DJ, Gawande AA, Bader AM. Surgery at the End of LifeThe Journal of the American Society of Anathesiologists Published online June, 2013.

Bowman KG, Jovic G, Rangel S, Berry WR, Gawande AA.Pediatric emergency and essential surgical care in Zambian hospitals: A nationwide studyJournal of Pediatric Surgery Published online June, 2013.

Rice-Townsend S, Gawande A, Lipsitz S, Rangel SJ.Relationship between unplanned readmission and total treatment-related hospital days following management of complicated appendicitis at 31 children’s hospitalsJournal of Pediatric Surgery Published online June, 2013.

Eappen S, Lane BH, Rosenberg B, Lipsitz SA, Sadoff D, Matheson D, Berry WR, Lester M, Gawande AA. Relationship Between Occurrence of Surgical Complications and Hospital FinancesJAMA April 17, 2013;309:1599-1606.

Kwok AC, Funk LM, Baltaga R, Lipsitz SR, Merry AF, Dziekan G, Ciobanu G, Berry WR, Gawande AA. Implementation of the World Health Organization Surgical Safety Checklist, Including Introduction of Pulse Oximetry, in a Resource-Limited SettingAnnals of Surgery April 4, 2013.

Molina G, Funk LM, Rodriguez V, Lipsitz SR, Gawande A.Evaluation of Surgical Care in El Salvador Using the WHO Surgical Vital StatisticsWorld Journal of Surgery Published online, March 2013.

Arriaga AF, Bader AM, Wong JM, Lipsitz SR, Berry WR, Ziewacz JE, Hepner DL, Boorman DJ, Pozner CN, Smink DS, Gawande AA. Simulation-Based Trial of Surgical-Crisis ChecklistsNew England Journal Of Medicine 2013;368:246-53.

Spector JM, Reisman J, Lipsitz S, Desai P, and Gawande AA.Access to Essential Technologies for Safe Childbirth: A Survey of Health Workers in Africa and AsiaBMC Pregnancy and Childbirth February 20, 2013;13:43-49.

Wong JM, Panchmatia JR, Ziewacz JE, Bader AM, Dunn IF, Laws ER, Gawande AA. Patterns in neurosurgical adverse events: intracranial neoplasm surgeryJournal of Neurosurgery 2012;33(5):E16.

Wong JM, Ziewacz JE, Ho AL, Panchmatia JR, Kim AH, Bader AM, Thompson BG, Du R, Gawande AA. Patterns in neurosurgical adverse events: open cerebrovascular neurosurgeryJournal of Neurosurgery 2012;33(5):E15.

GO TO the First article

http://gawande.com/articles

FIRST ARTICLE

Nanevicz TM, Prince MR, Gawande AA, Puliafito CA. Excimer laser ablation of the lens. Archives of Ophthalmology. 1986;104(12):1825-9.

Dr. Atul Gawande’s Articles in the New Yorker

States of Health
New Yorker
October 7, 2013

Slow Ideas
New Yorker
July 29, 2013

Why Boston’s Hospitals Were Ready
New Yorker
April 17, 2013

Big Med
New Yorker
August 6, 2012

Something Wicked This Way Comes
New Yorker
June 28, 2012

Failure and Rescue
New Yorker
June 4, 2012

200 Years of Surgery
New England Journal of Medicine
May 2, 2012
Documentary

Personal Best
The New Yorker
September 26, 2011

A Townie Speaks
Ohio University Commencement Address
June 11, 2011

Cowboys and Pit Crews
2011 Harvard Medical School Commencement Address
May 26, 2011

The Hot Spotters
The New Yorker
January 17, 2011

Seeing Spots
The New Yorker News Desk
January 27, 2011

Letting Go
The New Yorker
July 26, 2010
(citations)

Now What?
The New Yorker
Apr 5, 2010

Testing, Testing 
The New Yorker
Dec 14, 2009

The Cost Conundrum Redux
The New Yorker
News Desk Blog
Jun 23, 2009

The Cost Conundrum 
The New Yorker
Jun 1, 2009

Hellhole
The New Yorker
Mar 30, 2009

Getting There from Here 
The New Yorker
Jan 26, 2009

The Itch 
The New Yorker
Jun 30, 2008

A Lifesaving Checklist 
The New York Times
Dec 30, 2007

The Checklist 
The New Yorker
Dec 10, 2007

Sick and Twisted
The New Yorker
Jul 23, 2007

The Obama Health Plan
The New York Times
May 31, 2007

A Katrina Health Care System 
The New York Times
May 26, 2007

Rethinking Old Age
The New York Times
May 24, 2007

Let’s Talk About Sex 
The New York Times
May 19, 2007

Doctors, Drugs, and the Poor 
The New York Times
May 17, 2007

Bad Medicine, Sneaking In 
The New York Times
May 12, 2007

Curing the System
The New York Times
May 10, 2007

Can This Patient Be Saved? 
The New York Times
May 5, 2007

The Power of Negative Thinking
The New York Times
May 1, 2007

The Way We Age Now 
The New Yorker
Apr 30, 2007

The Score
The New Yorker
Oct 9, 2006

The Malpractice Mess
The New Yorker
Nov 14, 2005

Piecework
The New Yorker
Apr 4, 2005

The Bell Curve
The New Yorker
Dec 6, 2004

The Mop-Up
The New Yorker
Jan 12, 2004

Desperate Measures
The New Yorker
May 5, 2003

Cold comfort
The New Yorker
Mar 11, 2002

The learning curve
The New Yorker
Jan 28, 2002

The man who couldn’t stop eating
The New Yorker
Jul 9, 2001

Final cut
The New Yorker
Mar 19, 2001

Crimson tide

The New Yorker

Feb 12, 2001

Under suspicion
The New Yorker
Jan 8, 2001

When good doctors go bad
The New Yorker
Aug 7, 2000

GO TO the First article

FIRST ARTICLE
The Gist: Persian Gulf War Syndrome
The Gist
Slate
Oct 25, 1996
BOOKS

THE CHECKLIST MANIFESTO

A New York Times Bestseller and an Amazon Best Book of the Month: December 2009

http://gawande.com/the-checklist-manifesto

BETTER
One of Amazon.com’s 10 Best Books of 2007
Complications
“Essential Reading For Anyone Involved In Medicine”–Amazon.com –  2002

Part Two: The Retired Pathologist 

On Science, Medicine and HealthCare Policy – The Best Writers Among the WRITERS

Roles at http://pharmaceuticalintelligence.com

Chief Scientific Officer, Member of the Board

Research Categories OWNER:

  • Biomarkers & medical diagnosis in Pathology (Co-Owner)
  • Clinical Trials and IRB related Issues
  • Acute and Chronic Disease Classifications
  • Biomarker Discovery and Validation
  • Cardiovascular Research
  • Clinical Laboratory-Related Issues
  • Healthcare and Hospital Costs
  • Health Information Technology  and Workflow Redesign
  • Metabolomics
  • Metabolic Derangements
  • Nutraceuticals
  • Nutrigenomics
  • Nutrition
  • Nutrition and Phytochemistry
  • Proteomics
  • Statistical Methods for Research Evaluation
  • Systemic Inflammatory Response Related Disorders

 

Larry H. Bernstein, M.D., FCAP - My Life in Medicine 

www.linkedin.com/pub/larry-h-bernstein/a/599/50

I retired from a five year position as Chief of the Division of Clinical Pathology (Laboratory Medicine) at  New York Methodist Hospital-Weill Cornell Affiliate, Park Slope, Brooklyn in 2008 folowed by an interim consultancy at Norwalk Hospital in 2010.  I then became engaged with a medical informatics project called “Second Opinion” with Gil David and Ronald CoifmanEmeritus Professor and Chairman of the Department of Mathematics in the Program in Applied Mathematics at Yale.  I went to Prof. Coifman with a large database of 30,000 hemograms that are the most commonly ordered test in medicine because of the elucidation of red cell, white cell and platelet populations in the blood.  The problem boiled down to a level of noise that exists in such data, and developing a primary evidence-based classification that technology did not support until the first decade of the 21st century.

Realtime Clinical Expert Support and Validation System

Gil David and Larry Bernstein have developed, in consultation with Prof. Ronald Coifman, in the Yale University Applied Mathematics Program, a software system that is the equivalent of an intelligent Electronic Health Records Dashboard that provides empirical medical reference and suggests quantitative diagnostics options.

Our dashboard is a visual display of essential metrics. The primary purpose is to gather medical information, generate metrics, analyze them in realtime and provide a differential diagnosis, meeting the highest standard of accuracy. The diagnosis provides a risk assessment to the patient’s medical condition, while locating and presenting similar cases of other patients with the same anomalous profile and their corresponding treatment and followup. Given medical information of a patient, the system builds its unique characterization and provides a list of other patients that share this unique profile, therefore utilizing the vast aggregated knowledge (diagnosis, analysis, treatment, etc.) of the medical community.

The main mathematical breakthroughs are provided by accurate patient profiling and inference methodologies in which anomalous subprofiles are extracted and compared to potentially relevant cases. Our methodologies organize numerical medical data profiles into demographics and characteristics relevant for inference and case tracking. As the model grows and its knowledge database is extended, the diagnostic and the prognostic become more accurate and precise.

We anticipate that the effect of implementing this diagnostic amplifier would result in higher physician productivity at a time of great human resource limitations, safer prescribing practices, rapid identification of unusual patients, better assignment of patients to observation, inpatient beds, intensive care, or referral to clinic, shortened length of patients ICU and bed days.

[Second Opinion 2009-2011 Proprietary]

As an example, inputs from test data such as Hematology results are processed for anomaly characterization and compared with similar anomalies in a data base of 30,000 patients, provide diagnostic statistics, warning flags , and risk assessment . These are based on past prior experience , including ,diagnostics and treatment outcomes (collective experience). The system was trained on this database of patients, built the learning knowledge base and used to analysis and diagnosis 5,000 new patients. Our system identified successfully the main risks with very high accuracy (more than 96%) and very low false rate (less than 0.5%).

The main benefit is a real time assessment as well as diagnostic options based on

comparable cases, flags for risk and potential problems as illustrated in the following case acquired on 04/21/10. The patient was diagnosed by our system with severe SIRS at a grade of .61 .

The patient was treated for SIRS and the blood tests were repeated during the following week. Following treatment, the SIRS risk as a major concern was eliminated and the system provides a positive feedback for the treatment of the physician.

To experiment with our demo system using our existing database or your own data it  resides online at:

http://netlab2.math.yale.edu:30049/cgi-bin/second opinion.py

[Second Opinion 2009-2011 Proprietary]

I have been reviewing manuscripts somewhat frequently for Nutrition, Clin Chem Lab Med, Clin Biochem, and J Ped Hem Oncol., and serve on the Editorial Advisory Board of Nutrition.

I was the Chief, Clinical Pathology at NY Methodist Hospital, a 600+ bed hospital in Park Slope, Brooklyn, 2 hours from Bridgeport, CT, where I worked for 5 years,  and was previously Chief of Clinical Chemistry and Chief of Blood Bank at Bridgeport Hospital for 20 years, and Acting Chairman of Yale University Department of Pathology at Bridgeport Hospital for one year prior to my experience at NY Methodist Hospital Weill-Cornell.

My work with nutrition is extensive as a consulting pathologist on the Nutritional Support Team and I worked closely with the Burn Unit at Bridgeport Hospital, led by Dr. Walter Pleban, the first physician expert in burn and wound care to use TPN in Connecticut.  I rejected the dependence on serum albumin and implemented the first use of prealbumin (transthyretin)(half-life of 2 days) to follow the return to anabolic status of severely stressed patients, starting with Immunodiffusion plates from Behring Diagnostics, then converting to running batch turbidimetric assays on the Roche centrifugal analyzer, and finally running on a Beckman. My lab was the only one to get down to reliable measurements of 20 mg/L.  I co-chaired the First International Transthyretin Congress in Strasbourg, chaired the 14th and was an invited participant in the 17th Ross Roundtable on Nutrition, Organized and Chaired the Beckman Roundtable on Prealbumin in Los Angeles, was responsible for the AACC first document of Standards of Clinical Laboratory Practice with Lawrence Kaplan, and was recipient of the Labbe/Garry award of the Nutrition Division of AACC).  I did some of the earliest work on point of care diagnostics in neonatal care. My work with Creatine kinase isoenzyme MB and the isonzyme 1 of LD goes back to my residency and my long term contact with Burton Sobel. The improved use of troponins and NT-proBNP and have  been ongoing projects for the last 10 years, some of which was supported by Roche Diagnostics on the recommendation of Pauline Lau and Bernard Statland. The projects in normalizing the NT-proBNP for age and estimated glomerular filtration rate (eGFR), was successful, but widespread implementation is even more gradual than was TTR.

I have served on the Board of Directors of NAACLS and the American Library Association Commission on Accreditation, am listed in America’s Top Physicians, Marquis Who’s Who in Science and Engineering and Marquis’ Who’s Who in Medicine, Who’s Who in Pathology, Continental Who’s Who, Strathmore’s Who’s Who, and have 3 patents.

BIO
Selected Peer Reviewed publications

1. Rosser A. Rudolph, Larry H. Bernstein,and Joseph Babb. Information Induction for
Predicting Acute Myocardial Infarction. CLIN CHEM 1988; 34(10): 2031-2038.

2. Zarich SW, Bradley K, Mayall ID, Bernstein LH. Minor elevations in troponin T values enhance risk assessment in emergency department patients with suspected myocardial ischemia: analysis of novel troponin T cut-off values. Clin Chim Acta 2004; 343:223-29.

3. Bernstein, L.H.; Devakonda, A.; Engelman, E.; Pancer, G.; Ferrara, J.; Rucinski, J.; Raoof, S.; George, L.; Melniker, L. The Role of Procalcitonin in the Diagnosis of Sepsis and Patient Assignment to Medical Intensive Care.  J Clinical Ligand Assay, 2007; 30 (3-4):98-104

Older patients, make up a large part of the ICU population and tend to have an acute stressful condition superimposed on chronic illness.  The effects of anorexia, hypermetabolism, and malabsorption on these patients lead to substantial nitrogen losses. The most widely used methods for assessing malnutrition are the Subjective Global Assessment (SGA); TTR, and a combination of laboratory and biochemical features. The simplest of these, transthyretin (TTR) has become a commonly assayed protein in assessing PEM status. Clinical studies indicate that determination of the TTR level may allow for earlier recognition of malnutrition risk and timely intervention. Since TTR has a relatively short circulating half-life, it is expected to respond rapidly in response to metabolic support. TTR production decreases after 14 days of consuming a diet that provides only 60% of required proteins. Rapid turnover proteins, such as transthyretin (half-life < 2 days) respond early to nutrition support, and reflect a delayed return to anabolic status.It is particularly helpful in removing interpretation bias, and it is an excellent measure of the systemic inflammatory response concurrent with a preexisting state of chronic inanition. In the ICU patients we studied, TTR removed interpretation bias because the sickest patients experienced an uncommon delayed return of TTR to normal levels with adequate nutritional support.
DevakondaA, et al,Transthyretin as a marker to predict outcome in critically ill patients,ClinBiochem(2008),doi:10.1016/j.clinbiochem.2008.06.016
Protein energy malnutrition; Critically ill patients; Stress hypermetabolism; Transthyretin;  Multivariate classification.

4. Bernstein LH, Zions MY, Haq SA, Zarich S, Rucinski J, Seamonds B, Berger S, Lesley DY, Fleischman W, Heitner JF: Effect of renal function loss on NT-proBNP level variations. Clin Biochem; 2009;42(10-11):1091-8 [PMID: 19298805]

OBJECTIVE: NT-proBNP level is used for the detection of acute CHF and as a predictor of survival. However, a number of factors, including renal function, may affect the NT-proBNP levels. This study aims to provide a more precise way of interpreting NT-proBNP levels based on GFR, independent of age. METHODS: This study includes 247 pts in whom CHF and known confounders of elevated NT-proBNP were excluded, to show the relationship of GFR in association with age. The effect of eGFR on NT-proBNP level was adjusted by dividing 1000 x log(NT-proBNP) by eGFR then further adjusting for age in order to determine a normalized NT-proBNP value. RESULTS: The normalized NT-proBNP levels were affected by eGFR independent of the age of the patient. CONCLUSION: A normalizing function based on eGFR eliminates the need for an age-based reference ranges for NT-proBNP.
Kidney Function Tests. Natriuretic Peptide, Brain / blood. Peptide

5. David G, Bernstein LH, Coifman RR.  Generating Evidence Based Interpretation of Hematology Screens via Anomaly Characterization. The Open Clinical Chemistry Journal, 2011; 4:10-16. ISSN 1874-2416/11. Bentham Journal.
Introduction: We propose an automated nutritional assessment (ANA) algorithm that provides a method for malnutrition risk prediction with high accuracy and reliability. Materials  and Methods: The database used for this study is a file of 432 patients, where each patient is described by 4 laboratory parameters and 11 clinical parameters. A malnutrition risk assessment of low (1), moderate (2) or high (3) was assigned by a dietitian for each patient. An algorithm for data organization and classification via characteristic metrics is proposed.  For each patient, the algorithm characterizes its unique profile and builds a characteristic metric to identify similar patients who are mapped into a classification. Results: The algorithm assigned a malnutrition risk level for each patient based on different training sizes that were taken out of the data. Our method resulted in an average error (distance between the automated score and the real score) of 0.386, 0.3507, 0.3454, 0.34 and 0.2907 for 10%, 30%, 50%, 70% and 90% training sizes, respectively. Our method outperformed the compared method even when our method used a smaller training set then the compared method. In addition, we show that the laboratory parameters themselves are sufficient for the automated risk prediction and adding the clinical parameters does not improve the accuracy. We present an organization of the patients into several clusters and sub-clusters. These  clusters  correspond to low risk areas, low-moderate risk areas, moderate risk areas, moderate-high risk areas and high risk areas. The organization and visualization methods provide a tool for exploration and navigation of the data points. Discussion: The problem of rapidly identifying risk and severity of malnutrition is crucial for minimizing medical and
surgical complications associated with previsit under-nutrition, chronic illness affecting swallowing, eating, and weight loss.

6. Brugler L, Stankovic AK, Schlefer M, Bernstein L. A simplified nutrition screen for hospitalized patients using readily available laboratory and patient information. Nutrition 2005; 21(6): 650-658

Results:  The analysis demonstrated the characteristics that correlated best with MRC risk level assignment were: the occurrence of a wound (p=2.5e-14), poor oral intake (p=3.2e-14), malnutrition related admission diagnosis (p=3.9e-9), serum albumin value (p=1.4e-31), hemoglobin value (p=3.3e-10), and total lymphocyte count   (p=1.4e-29). The 6 variable model had an R2 of 0.773 and p = 4.6e-116. A second model had 4 variables (malnutrition related admission diagnosis, serum albumin value, hemoglobin value and total lymphocyte count) and 3 (high, moderate and low) versus 4 (high, moderate, low and no) MRC risk levels with an R2 of 0.721 and p = 1.6e-104. Discussion: The ability of admission information to accurately reflect MRC risk is crucial to early initiation of restorative medical nutrition therapy (MNT), the efficient utilization of nutrition care resources and compliance with regulatory requirements. There is currently no uniform or proved standard for identifying MRC risk within 24 hours of acute care admission. The ideal nutrition screen correlates well with the occurrence of MRCs and also contains parameters that can be quickly and routinely obtained at admission. The six and even four parameter models described above meet both criteria and they can be uniformly used by hospitals to screen patients for MRC risk.7. Larry H. Bernstein, and James Rucinski. The relationship between granulocyte maturation and theseptic state measurement of granulocyte maturation may improve the early  diagnosis of the septic state,   Clin Chem Lab Med 2011;49   DOI 10.1515/CCLM.2011.688

Methods: This study calibrates and validates the measurement of granulocyte maturation with Immature granulocytes (IG) to the identification of sepsis, a study carried out on a
Sysmex Analyzer, model XE 2100 (Kobe, Japan). The Sysmex IG parameter is a crucial measure of immature granulocyte counts and includes metamyelocytes and myelocytes,
but not band neutrophils. Results and conclusions: We found agreement with previous work that designated an IG measurement cut-off of 3.2  as optimal. The analysis was then carried a step further with a multivariable discriminator.

8. Larry H Bernstein and Johannes Everse. Studies on the Mechanism of the Malate Dehydrogenase Reaction. J Biol Chemistry.  Dec 25, 1978; 253(24): 8702-8707.

These studies determine the levels of malate dehydrogenase isoenzymes in cardiac muscle by a steady state kinetic method which depends on the differential inhibition of these isoenzyme forms by high concentrations of oxaloacetate. This inhibition is similar to that exhibited by lactate dehydrogenase in the presence of high concentrations of pyruvate. The results obtained by this method are comparable in resolution to those obtained by CM-Sephadex fractionation and by differential centrifugation for the analyses of mitochondrial malate dehydrogenase and cytoplasmic malate dehydrogenase in tissues. The use of standard curves of percent inhibition of malate dehydrogenase activity plotted against the ratio of mitochondrial MDH activity to the total of mMDH and cMDH activities [ malate dehydrogenase ratio] (percent m-type) is introduced for studies of comparative mitochondrial function in heart muscle of different species or in different tissues of the same species.

9. MB Grisham, LH Bernstein, J Everse. The cytoplasmic malate dehydrogenase in neoplastic tissues” presence of a novel isoenzyme? Br J Cancer 1983; 47: 727-731

Malate dehydrogenase (MDH,EC1.1.1.37) catalyzes the reversible reduction of oxaloacetate tomalate in the presence of NADH. In eukaryotic cells the enzyme is generally found to be present as two distinct isoenzymes; one form is present in the cellular cytosol and the other is present exclusively in the mitochondria. These 2 isoenzymes form part of a shuttle system (the malate-aspartate shuttle) that functions as the major mechanism for the transportation of reducing equivalents between the cytosol and the mitochondria. As part of our ongoing studies on the mechansim of action and metabolic function of the malate dehydrogenases (Bernstein,etal. 1978; Bernstein & Everse, 1978; Bernstein & Grisham 1978), we recently
investigated the kinetic properties of the 2 isoenzymes present in rat Novikoff hepatoma tissues.These studies were initiated to evaluate whether or not the enzymes in the malate-asparate shuttle of tumour tissues are structurally and functionally identical to those of normal tissues. Fresh tumour or liver was homogenized with a glass tissue homogenizer in 0.1M potassium phosphate buffer, pH 7.5, containing 0.25M sucrose, centrifuged to remove tissue debris, and the supernatant was then centrifuged to obtain a supernatant that contained the cytoplasmic enzymes. The supernatantant did not contain any isocitrate dehydrogenase activity or transhydrogenase activity and was therefore judged to be free of mitochondrial enzymes.This high-speed supernatant was used without further fractionation for the determination of the cytoplasmic MDH activity. Mitochondria were prepared by suspending the pellet in 0.1M phosphate buffer, pH7.5, containing 0.25M sucrose and centrifuging the suspension at 600 g,  and re-centrifuged at 20,000 g for 30 min, and the precipitate was collected and washed, then suspended in phosphate buffer and sonicated for 1 min. The resulting solution was used for the assays for the mitochondrial enzyme. The assays were performed in 0.1M phosphate buffer, pH 7.0, at room temperature with a Beckman Model 24 recording spectrophotometer. We found that the Km values of the mitochondrial enzyme from the hepatoma tissue were identical with the values obtained with the enzyme from normal liver mitochondria. The cytoplasmic enzymes also have identical Km values for the coenzyme; however,the Lineweaver-Burk plots for oxaloacetate were non-identical. Whereas the Km value for oxaloacetate obtained with the liver enzyme was- 55 M, the Lineweaver-Burk plot obtained with the hepatoma enzyme displayed 2 slopes. One of the slopes corresponded with a Km value that is approximately identical to that of the liver enzyme, whereas the other slope yielded a Km value for oxaloacetate of-1mM. We interpret these data to indicate that Novikoff hepatoma tissue contains 2 cytoplasmic enzymes that possess MDH activity, one of which closely resembles that present in the rat liver cytoplasm. The other enzyme, having a Km of-1mM, is not found in normal liver tissue.

Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View?

Author: Larry H. Bernstein, MD, FCAP  

Article Published 10/17/2012 — 4,111 VIEWS on 12/10/2013

Top Author Views in 12 mo
larryhbern 40,730

Electronic Books EDITORIAL 

Series A: e-Books on Cardiovascular Diseases

Content Consultant: Justin D Pearlman, MD, PhD, FACC

Volume One: Perspectives on Nitric Oxide

Sr. Editor: Larry Bernstein, MD, FCAP, Editor: Aviral Vatsa, PhD and Content Consultant: Stephen J Williams, PhD

available on Kindle Store @ Amazon.com

http://www.amazon.com/dp/B00DINFFYC

Volume Two: Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation

Curators: Justin D Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP, Aviva Lev-Ari, PhD, RN

  • Causes
  • Risks and Biomarkers
  • Therapeutic Implications

Volume Three: Etiologies of CVD: Epigenetics, Genetics & Genomics

Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

  • Causes
  • Risks and Biomarkers
  • Therapeutic Implications

Genomics and Medicine by Prof. Marcus Feldman, Stanford University

Volume Four: Therapeutic Promise: CVD, Regenerative & Translational Medicine

Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

  • Causes
  • Risks and Biomarkers
  • Therapeutic Implications

Volume Five: Pharmaco-Therapies for CVD

Curators: Vivek Lal, MD, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

  • Causes
  • Risks and Biomarkers
  • Therapeutic Implications

Volume Six: Interventional Cardiology and Cardiac Surgery

Curators: Justin D Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP, Aviva Lev-Ari, PhD, RN

  • Causes
  • Risks and Biomarkers
  • Therapeutic Implications

Volume Seven: CVD Imaging for Disease Diagnosis and Guidance of Treatment

Author, Curator and Editor: Justin D Pearlman, MD, PhD, FACC and Article Curator: Aviva Lev-Ari, PhD, RN

  • Causes
  • Risks and Biomarkers
  • Therapeutic Implications

Series B: e-Books on Genomics & Medicine

Content Consultant: Larry H Bernstein, MD, FCAP

Volume 1: Genomics and Individualized Medicine

Sr. Editor: Stephen J Williams, PhD

Editors: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Volume 2: Methodological Breakthroughs in NGS

Editor: Marcus Feldman, PhD, Prof. of Genetics, Stanford University

Volume 3: Institutional Leadership in Genomics

Editors: Marcus Feldman, PhD and Aviva Lev-Ari, PhD, RN 

Series C: e-Books on Cancer & Oncology

Content Consultant: Larry H Bernstein, MD, FCAP

Volume 1: Cancer and Genomics

Sr. Editor: Stephen J Williams, PhD

Editors: Ritu Saxena, PhD, Tilda Barliya, PhD

Volume 2: Radiation Oncology & Immunotherapy in Cancer

Sr. Editor: Sidney P. Kadish, MD, Fellow American College of Radiology (FACR), Professor of Radiation Oncology and Radiology, University of Massachusetts Medical School and UMass Memorial Medical Center

Editors: Stephen J Williams, PhD, Dror Nir, PhD and Tilda Barliya, PhD

Volume 3: Nanotechnology and Drug Delivery

Editor and Author: Tilda Barliya, PhD

Series D: e-Books on BioMedicine

Volume 1: Metabolomics

Sr. Editors: Larry H Bernstein, MD, FCAP and

Editor: Ritu Saxena, PhD 

ARTICLES on http://pharmaceuticalintelligence.com

12/10/2013: 276 Scientific Articles
FIRST Article on This Open Access Scientific Journal, 7/28/2013, 569 Views:

The role of biomarkers in the diagnosis of sepsis and patient management

L. H. Bernstein, MD, FCAP

LIST of 276 ARTICLES on http://pharmaceuticalintelligence.com

Recommended Reading by the Curator of this article:

The Essential Role of Nitric Oxide and Therapeutic NO Donor Targets in Renal Pharmacotherapy

 

Author’s Selection of his Top Articles to date on the Journal

  • Developments in the Genomics and Proteomics of Type 2 Diabetes Mellitus and Treatment Targets

http://pharmaceuticalintelligence.com/2013/12/08/developments-in-the-genomics-and-proteomics-of-type-2-diabetes-mellitus-and-treatment-targets/

  • Vegan Diet is Sulfur Deficient and Heart Unhealthy
  • Erythropoietin (EPO) and Intravenous Iron (Fe) as Therapeutics for Anemia in Severe and Resistant CHF: The Elevated N-terminal proBNP Biomarker

Read Full Post »


Updated: Investing and Inventing: Is the Tango of Mars and Venus Still on

Curator: Aviva Lev-Ari, PhD, RN

UPDATED on 4/15/2014

14th ANNUAL BIOTECH IN EUROPE FORUM For Global Partnering & Investment
30th September – 1st October 2014 • Congress Center Basel

SACHS Associates, London

http://www.sachsforum.com/zurich14/index.html

 

UPDATED on 4/15/2014

New Trends in Investing and Inventing: Who Benefits from the Booming Success of the Technology Industry

INVESTMENT BANKING, TECHNOLOGY, VENTURE CAPITAL, INITIAL PUBLIC OFFERINGS, SILICON VALLEY (CALIF), START-UPS

The dealbook.nytimes.com reported in 4/13/2014 the following IPO related and Start up Cases that exemplify the NEW trends

by Sydney Emner with Comments of Scott Kupor, Managing Partner at Andreessen Horowitz.

  • “There’s a broader public policy question here,” Mr. Kupor said. “There is a wealth transfer happening, from public investors to private investors. And the benefits are accruing to the investors that can access the private markets.”
  • Of the 100 largest venture capital rounds on record, 88 were issued within the past five years, according to CrunchBase, which tracks venture funding. Each delivered more than $50 million to the companies.
  • Proliferation of big late-stage investments: The average size of such investments so far this year was $44.1 million, the highest level in the past five years and up 77 percent from last year, according to data from CB Insights.
  • Technology start-ups are staying private longer
  • Venture capital firms are looking to put idle funds to work, and
  • Institutional investors are chasing returns in fast-growing private companies
  • Megarounds, the flood of money is inflating the valuations of early-stage companies. companies are collecting the additional money simply because they can, taking advantage of an ocean of ready cash
  • Over valuations may lead to yet another dot-com bubble 2014 vs 2001
  • For venture capitalists, allowing portfolio companies to take on more funding means their existing stakes can be diluted. But since these big rounds often lead to much higher valuations, many investors don’t mind
  • Partner at Sequoia Capital, conceded that investors were spending less and less time conducting due diligence: playing by slightly different rules than what happened even five years ago
  • In recent years the sheer amount of capital available for investment in Silicon Valley start-ups went up: big venture capital firms have recently raised big rounds, meaning the traditional backers of tech firms are well positioned to write big checks
  • Venture capitalists are increasingly being joined by hedge funds and private equity firms chasing huge returns. Among the top investors in fund-raising rounds that collected over $100 million are
  1. Digital Sky Technologies and
  2. Tiger Global Management, which ranked alongside traditional venture capital firms like
  3. Andreessen Horowitz and
  4. Kleiner Perkins Caufield & Byers, according to CB Insights
  1. T. Rowe Price and
  2. Fidelity Investments.
  3. JPMorgan

“Appreciation that normally would have happened in the public market is happening in the private market,” said Mr. Kupor of Andreessen Horowitz. “This is why we see T. Rowe, Fidelity and JPMorgan investing. They’re saying, ‘There’s not a lot of growth for us in the public market.’ ”

  • In many cases, such firms are given access to promising start-ups with the understanding that they would remain investors even after an I.P.O.
  • Some hedge funds are even transforming themselves into so-called growth capital firms that invest in older start-ups. Coatue Management, for example, is planning on raising a $500 million fund devoted to the kinds of investments that the firm has made in companies like Snapchat.com and the last-minute hotel booking site HotelTonight.comDropbox.com  is another case in point
  • Instead of raising just enough money for the next 18 months or two years, companies are now raising all the money they could feasibly need as a private company in one fell swoop.“Today, companies can raise money well ahead of any actual need.” Mr. Fogelsong said.
  • Companies receiving the influxes of capital, having so much money in the bank allows them to control their own destiny, rather than be at the mercy of acquirers or the markets. “If someone wants to buy them, they can turn it down and wait for a higher price,” said Peter C. Wendell, managing director of Sierra Ventures. “If the I.P.O. is looking shaky, they can say, ‘Look at my balance sheet,’ and wait.”
  • The average age of companies going public today is 10 years, in contrast to the average of just six years in 2000, according to Jay R. Ritter, a professor at the University of Florida.
  • On average, between a quarter and just under a third of the late-stage money is being used to buy shares from employees and early investors ahead of an I.P.O.
  • “Rounds that would have otherwise gotten done in the public markets are getting done in the private markets,” said Scott Kupor, partner and chief operating officer of Andreessen Horowitz, a venture capital firm that is among the most active participants in big late-stage rounds.

Case Study #1: Quora.com

Quora, a question-and-answer website, didn’t need to raise money. It had barely touched $60 million in venture capital that it accepted just two years ago. Yet the California company, which has no revenue and just 70 employees, recently announced that it had raised an additional $80 million. The new round valued the company at a reported $900 million, more than double the previous valuation of $400 million. That means that while some early investors may have seen their ownership diluted by the new round, the value of their holdings nonetheless soared.  “When it goes off at a high price, the V.C. gets to change the price of the other stock on his books,” said Mr. Wendell of Sierra Ventures. The result is that much of a company’s gain in value is happening before it even goes public.

Case Study #2: Nextdoor.com

Silicon Valley expression: Eat when the food is passed,” said Nirav Tolia, chief executive of Nextdoor, which last year accepted $60 million in additional venture funding despite having plenty of money in the bank. . “It’s always good to bet on the furthest-out point.” per Mr. Tolia

Case Study #3: Airbnb.com

Airbnb, the home-sharing site, neared a deal to raise as much as a staggering $500 million from investors like TPG Growth, T. Rowe Price and Dragoneer Investment Group, according to people briefed on the matter. TPG Growth alone had been prepared to provide up to $150 million in the round, one of these people said

Case Study #4: Uber.com and Lyft.com

And two weeks ago, Lyft raised $250 million from the likes of the Alibaba Group of China and Daniel S. Loeb’s investment firm, Third Point — despite being widely regarded as significantly behind the leader in the car service industry, Uber.com

Longer incubation periods mean many companies do need more capital for operating expenses. For example, companies that focus on on-demand services, like the car ride companies Uber and Lyft, require capital as they build out their dispatch networks in new cities and offer new products.

Case Study #5: Fab.com

Fab.com, an e-commerce start-up that raised $150 million last summer at the tender age of two years. An overambitious expansion plan and falling sales led to a wave of employee exits and a painful retrenchment.

Case Study #6: Box.com

Box, the cloud storage company, has filed to go public at a time when, filings show, it needs to raise more capital. But its rival, Dropbox, recently raised $250 million and may put off its I.P.O., especially as appetite for technology stocks is faltering.

Case Study #7: HomeAway.com

In 2008, HomeAway, the real estate website, was planning to go public. But as the financial crisis began, HomeAway executives decided to postpone the I.P.O. Instead, in November of that year, HomeAway raised $250 million in additional venture capital and resolved not to think about going public for at least two years.  The company finally went public in 2011.

SOURCE

http://dealbook.nytimes.com/2014/04/13/rich-start-ups-go-back-for-another-helping/?_php=true&_type=blogs&emc=edit_dlbkam_20140414&nl=business&nlid=40094405&_r=0

 

UPDATED 3/1/2014

The 2nd ANNUAL Sachs Cancer Bio Partnering & Investment Forum Promoting Public & Private Sector Collaboration & Investment in Drug Development, 19th March 2014 • New York Academy of Sciences • USA

http://pharmaceuticalintelligence.com/2013/12/17/the-2nd-annual-sachs-cancer-bio-partnering-investment-forum-promoting-public-private-sector-collaboration-investment-in-drug-development-19th-march-2014-•-new-york-academy-o/#!

UPDATED on 1/10/2014

Biotech Showcase™ 2014

January 13-15, 2014 San Francisco, CA Parc 55 Wyndham, SF, Union Square

Program Overview

Investing and Inventing: Is the Tango of Mars and Venus Still on

Curator: Aviva Lev-Ari, PhD, RN

According to JERZY GANGISERIAL ENTREPRENEUR

Investing and inventing has become way too dogmatic:

  • Investors say, “We don’t fund ideas, we fund traction.”
  • Entrepreneurs say, “You never make a business plan. You only make an MVP.”
  • Investors say, “We like companies that are going to get acquired for $100M, not try to go for an IPO.”
  • Entrepreneurs say, “I’ll just aim for an acqui-hire or a small M&A deal, it’s much lower risk.”
  • Investors say, “We make a lot of small investments, instead of one or two that are potential home runs.

SOURCE

http://jerzygangi.com/why-silicon-valley-funds-instagrams-not-hyperloops/#!

This curation was conceived following the review on the following Sources:

Source # 1 

WHERE STARTUP FUNDING REALLY COMES FROM (INFOGRAPHIC)

By Laura Entis, November 20, 2013

Posted by Healthios Xchange Administrator Wed at 10:23 AM - 301 views – Filed in Healthios Selections

http://www.healthiosxchange.com/articles/1030/where-startup-funding-really-comes-from#!

Source #2

WHY SILICON VALLEY FUNDS INSTAGRAMS, NOT HYPERLOOPS

by JERZY GANGI SERIAL ENTREPRENEUR, August 19, 2013

http://jerzygangi.com/why-silicon-valley-funds-instagrams-not-hyperloops/#!

Source #3

Special Issue: Silicon Valley: Global model or unique anomaly by Social Science Information/SSI – A Sage Publicationsinternational  journal

Reporter: Aviva Lev-Ari, PhD, RN

Source #4

Innovators can exit with an idea: How to Monetizing Patents and ideas: yazamIP.com launches Idea Lab

Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/08/innovators-can-exit-with-an-idea-how-to-monetizing-patents-and-ideas-yazamip-com-launches-idea-lab/

Source #5

Connecting INVENTORS to BUSINESS BUILDERS and INVESTORS

Source #6

University-Industry Partnerships; NIH/DOD Funded Industry – Academic Collaborations

According to Source #1: Investing and inventing: Is the Tango of Mars and Venus Still on

Where Startup Funding Really Comes From (Infographic)

According to Source #2: Investing and inventing: Is the Tango of Mars and Venus Still on

Ten Theories explain the REALITY

THEORY 1: THE IPO MARKET SUCKSTHEORY 2: CONTEMPORARY PORTFOLIO STRATEGY FAVORS LAYUPS AND DISCOURAGES 3-POINTERS

THEORY 3: “WE DON’T FUND IDEAS”

THEORY 4: “minimally viable product” The MVP OBSESSION

THEORY 5: THE MARKET REWARDS EXITS, NOT INNOVATION AND VALUETHEORY 6: INVESTORS ARE TOO SPECIALIZED

THEORY 7: MOST ANGELS AND VC’S ARE WIMPS

Second 7 in the Original Article, thus,

  • 2nd 7 = Theory 8
  • Theory 8 = Theory 9
  • Theory 9 = Theory 10

THEORY 7: CORPORATE R&D AND CORPORATE TALENT RETENTION SUCKS, SO CORPORATE M&A IS HUNGRY

THEORY 8: FIRST-TIME ENTREPRENEURS CAN’T BE TRUSTED

THEORY 9: THE REAL REASON IS THAT WE’RE SHEEP

According to Source #3: The SILICON VALLEY Tango of Investing and inventing is Still on

Henry Etzkowitz

Silicon Valley at risk? Sustainability of a global innovation icon: An introduction

to the Special Issue

Social Science Information December 2013 52: 515-538,

doi:10.1177/0539018413501946

Doug Henton and Kim Held

The dynamics of Silicon Valley: Creative destruction and the evolution of the

innovation habitat

Social Science Information December 2013 52: 539-557,

doi:10.1177/0539018413497542

James C Williams

From white gold to silicon chips: Hydraulic technology, electric power and

Silicon Valley

Social Science Information December 2013 52: 558-574,

doi:10.1177/0539018413497834

Annika Steiber and Sverker Alänge

The formation and growth of Google: A firm-level triple helix perspective

Social Science Information December 2013 52: 575-604,

doi:10.1177/0539018413497833

Henry Etzkowitz

StartX and the ‘Paradox of Success’: Filling the gap in Stanford’s

entrepreneurial culture

Social Science Information December 2013 52: 605-627,

doi:10.1177/0539018413498833

Steven Casper

New-technology clusters and public policy: Three perspectives

Social Science Information December 2013 52: 628-652,

doi:10.1177/0539018413501236

Helen Lawton Smith, John Glasson, Saverio Romeo, Rupert Waters, and Andrew

Chadwick

Entrepreneurial regions: Evidence from Oxfordshire and Cambridgeshire

Social Science Information December 2013 52: 653-673,

doi:10.1177/0539018413499978

 

According to Source #4: Investing and inventing: Is the Tango of Mars and Venus Still on

 The IDEA as Entry and as Exit Point

1. yazamIP.com launches Idea Lab, enabling innovators to exit without necessarily establishing a startup.

If you: (A) have a track record of innovation and have a solution for a significant technical problem, and (B) are interested in either of the options below, both have no cost to you: (i) a $1,000,000 “exit” from your idea without necessarily leaving your “day-job”; (ii) having proven innovation, patent and business experts work with you to establish a robust patent portfolio based on your idea. And you maintain the option to spin off the strong portfolio into a startup for you to build the market.

Then yazamIP.com’s Idea Lab is for you. See http://www.yazamip.com/valuations

2. Tel Aviv University’s Ramot raises $17m from Tata & SanDisk.http://yazamip.com/node/84

3. Elvis Presley IP sells. http://yazamip.com/node/82

4. Innovation and patents are helping to increase gun sales.http://yazamip.com/node/85

Want to get a valuation on your patent? See http://yazamip.com/valuations

Do not forget to contact yazamIP.com to inquire about our most generous “referral a patent” fee arrangement.

NEWS AND DEVELOPMENTS1. yazamIP.com launches patent valuation service. http://www.yazamip.com/valuations2. yazamIP.com client initiates patent infringement action against Sony.http://www.yazamip.com/node/743. Twitter has only 9 patents pre-IPO, a fact that has investors worried.http://www.yazamip.com/node/734. Marijuana-related patents? Now that is a market to corner!http://www.yazamip.com/node/77
SERVICES
  1. If the companies are in distress and have US patents then we can sell them for the inventor
  2. If the patents are being infringed upon, we can see how we can help the inventor get compensated
  3. If the inventors have great ideas that they have not turned into companies yet, we would consider investing in them to convert the ideas into patent portfolios

According to Source #5: Connecting INVENTORS to BUSINESS BUILDERS and INVESTORS – Investing and inventing: Is the Tango of Mars and Venus Still on

National Venture Capital Association <http://www.nvca.org/>
DEN =http://www.den.dartmouth.edu/     http://www.den.dartmouth.edu/about/overview.html
Small Business Investment Companies (SBIC) <http://www.sba.gov/content/venture-capital-startups-high-growth-technology-companies>   programs by state
Directory of Angel-investor networks <http://www.inc.com/articles/2001/09/23461.html>
Tech Coast Venture Network <http://tcvn.org/>
Start-up Report posting service <http://www.startupreport.com/>
Hub Angels Investment Group, LLC <http://www.hubangels.com/>
Links to Angel networks in Midwest <http://www.northstareconomics.com/angel_investing.htm>
The San Diego Venture Group <http://www.sdvg.org/>
Angels in Arizona <http://www.arizonaangels.com/index.htm>
The Aurora Angels <http://www.auroraangels.com/>
Atlanta, Georgia, Angel network <http://angelatlanta.com/>
Valley Angel Investment Fund
<http://gust.com/angel-group/valley-angel-investment-fund> Ohio Angel network <http://www.c-cap.net/about.html>
Great Valley Pennsylvania Angel network <http://www.greatvalleyalliance.com/programs/paan.htm>
Vancouver, British Columbia Angel network <http://www.vef.org/>
Information and links to venture capital sources in China <http://www.chinasite.com/Business/VentureCapital.html>
Los Angeles Regional Technology Alliance <http://www.larta.org/>

According to Source #6:University-Industry Partnerships; NIH/DOD Funded Industry – Academic Collaborations - Investing and inventing: Is the Tango of Mars and Venus Still on

Presentation and Panel Discussion
 
University-Industry Partnerships; NIH/DOD Funded Industry – Academic Collaborations

The 9th Annual Non-Dilutive Funding Summit is proud to host Dr. Anthony Boccanfuso, Executive Director, The National Academies’ University-Industry Demonstration Partnership (UIDP) who will discuss in his presentation industry-academic collaborations and how the life science industry can leverage such ties to secure non-diltuive capital to fund their R&D activities.

Following the presentation, Dr. Boccanfuso will lead a panel discussion featuring top industry executives who will detail how non-dilutive funding substantially assisted in maintaining a sustainable business while promoting their R&D efforts.
 - REGISTRATION IS FREE OF CHARGE -
1:00 – 2:30
Presentation – University-Industry Partnerships
Presenter and Panel Moderator:
Anthony Boccanfuso
Executive Director, The National Academies’ University-Industry Demonstration Partnership (UIDP)


Panel Discussion
University-Industry Partnerships; NIH/DOD Funded Industry/Academic Collaborations
Dr. Eric Patzer
Founder and President, Aridis Pharmceuticals
Dr. Scott Thatcher
CEO & Founder, Orphagen
Dr. Timothy A Antaya
CEO, Antaya Science and Technology
James Knighton
CEO, AvidBiotics
Full Meeting Agenda
07:30 – 08:30
Pre-Conference Workshop – 1X1 RO1 for Companies
Ayal Ronen
Vice President, FreeMind Group
08:30 – 09:00 Breakfast and Networking
09:00 – 10:15
Welcome Presentation 

- Non-Dilutive Funding Forecast 2014

 

Ram May-Ron
Managing Partner, FreeMind Group
10:30 – 11:30
Keynote – National Heart, Lung, and Blood Institute (NHLBI; NIH) Presentation: “Navigating the Transition from Discovery to Market” 
Dr. Jodi Black
Deputy Director, Division of Extramural Research Activities, National Heart, Lung, and Blood Institute, NIH
11:30 – 12:00 NIH Round Table Discussion – Meet with NHLBI OfficialsDr.JodiBlackDeputy Director, Division of Extramural Research Activities, National, Heart, Lung, and Blood Institute,NIHLarryMahanDirector, Office of Translational Alliances & Coordination at National Heart, Lung, and Blood Institute, NIH
12:00 – 1:00 Break
1:00 – 2:30
Presentation – University-Industry Partnerships
Presenter and Panel Moderator:
Anthony Boccanfuso
Executive Director, University-Industry Demonstration Partnership (UIDP)


Panel Discussion
University-Industry Partnerships; NIH/DOD Funded Industry/Academic Collaborations
Dr. Eric Patzer
Founder and President, Aridis Pharmceuticals
Dr. Scott Thatcher
CEO & Founder, Orphagen
Dr. Timothy A Antaya
CEO, Antaya Science and Technology
James Knighton
CEO, AvidBiotics
2:30 – 3:00 Coffee Break
3:00 – 3:30 Meet the Expert – Round Table Discussions

Neurological Disorders Funding Opportunities

Guy Har-Chen
Chief Analyst, FreeMind Group

3:30 – 4:00 Meet the Expert – Round Table Discussions

Infectious Diseases and Biodefense Funding Opportunities
Guy Har-Chen
Chief Analyst, FreeMind Group
4:00 – 4:30 Closing Remarks
SOURCE 

This email was sent to avivalev-ari@alum.berkeley.edu by carla@freemindconsultants.com |
FreeMind Group | 423 Brookline Avenue #124 | Boston | MA | 02215 

617-648-0340 ext 249

CONCLUSIONS

by Aviva Lev-Ari, PhD, RN

  • Investing and inventing is a Market Place as well as a Profession. Market places are typified by information imperfection and Professions are typified by very steep Specialization and Competition
  • I am in full agreement with the comment made by

Stephen J. Williams, Ph.D.

Stephen J. Williams, Ph.D, Cancer Pharmacologist, Expert, Author, Writer and Senior Editor @ http;//pharmaceuticalintelligence.com
“Quite interesting that average family and friends investment is $23,000. I wonderhowtheywereabletoseperateoutcrowdfunding, angel investors, from family and friends. I also wonder whattherateofincreasewithcrowdfunding is? However equally surprising is that VC does not make that much of initial startup funding. I think banks level of funding have steadily decreased since the consolidation of the 90′s.”

  • I followed the advice of Dr. Dror Nir and I perfectly agree with his observation on the relevance of the Ten Theories by  JERZY GANGI, SERIAL ENTREPRENEUR

Dror Nir
Dror Nir, Managing partner at RadBee, Expert, Author, Writer, Editor and Top Contributor to LinkedIn Group: Leaders in Pharmaceutical Business Intelligence

“I think you should read this, there are interesting insights which I very much agree with.”
http://jerzygangi.com/why-silicon-valley-funds-instagrams-not-hyperloops/

  • Innovators can exit with an idea: How to Monetizing Patents and ideas: yazamIP.com launches Idea Lab. yazamIP.com launches Idea Lab, enabling innovators to exit without necessarily establishing a startup. This is a desruptive technology with great potential designed to solve problems emerging from the Ten theories of the dogmatic nature of the interplay between Investors and Entrepreneurs who are either the Inventors or the Team members of Start ups.
  • I agree with JERZY GANGI, SERIAL ENTREPRENEUR that Investing and inventing has become way too dogmatic:
    • Investors say, “We don’t fund ideas, we fund traction.”
    • Entrepreneurs say, “You never make a business plan. You only make an MVP.”
    • Investors say, “We like companies that are going to get acquired for $100M, not try to go for an IPO.”
    • Entrepreneurs say, “I’ll just aim for an acqui-hire or a small M&A deal, it’s much lower risk.”
    • Investors say, “We make a lot of small investments, instead of one or two that are potential home runs.
  • Source #1 – is a MUST information to be mastered by both Investors and Entrepreneurs
  • The ten theories are very insightful, they mirror my own views on  Investing and inventing as is manifested in the US and in other Developed countries.
  • Angel Investment is there to stay and is the MOST sensitive source of funding affected by volatility in economic markets conditions. Source #5 was add as an endorsed suggestion made by Dr. Justin D Pearlman, MD, PhD, FACC an Expert, Author, Writer, Editor @ http://pharmaceuticalintelligence.com, a Patent holder and an Inventor at Leaders of Pharmaceutical Business Intelligence
  • Silicon Valley is where I lived, 1978 – 1990 (Palo Alto), pursued Graduate studies (UC, Berkeley, Stanford GSB) and worked as an Executive in the Largest Think Tank in the US, SRI International, and at Amdahl Corporation, Sunnyvale, CA]. The SIlicon Valley is not an anomaly but a Singular point in the Entrepreneurship Ecosystem.
  • Silicon Valley is being followed by another Singular point driven by and derived from a different ethos and impatus, namelythe ecosystem in the “Start ups Nation” Israel.
  • Israel is different than the Silicon Valley in CA, or any other Start ups hub in the US.
  • I am in full agreement, based on my own experience as an Israeli resident in Israel, 1958 – 1978, with the differences and the unique reasons for the Israeli success, as presented  in

Start-up Nation: The Story of Israel’s Economic Miracle by Dan Senor (Author), Saul Singer (Author)
http://www.amazon.com/Start-up-Nation-Israels-Economic-Miracle/dp/0446541478

Other related articles published on this Open Access Online Scientific Journal include the following:

 

 

Read Full Post »

Older Posts »

Follow

Get every new post delivered to your Inbox.

Join 1,306 other followers