Healthcare analytics, AI solutions for biological big data, providing an AI platform for the biotech, life sciences, medical and pharmaceutical industries, as well as for related technological approaches, i.e., curation and text analysis with machine learning and other activities related to AI applications to these industries.
FIG. 3. Regulation of ER calcium homeostasis by the BCL-2 protein family. Different anti- and proapoptotic members of the BCL-2 family of proteins are located at the ER membrane, where they have an important role regulating ER calcium content. BCL-2 and BCL-XL interact with the IP3R calcium channel, modulating its activity. BCL-2 has been shown to increase ER calcium leak through the IP3R because of an increase on its phosphorylation levels.
BAX and BAK have the opposite effect on ER calcium content, a function that may be further modulated by BH3-only proteins (such as PUMA and BIK). In addition, the activity of BCL-2 at the ER membrane is regulated by phosphorylation. JNK phosphorylates BCL-2, decreasing its antiapoptotic activity and increasing ER calcium content, whereas the phosphatase PP2A decreases this phosphorylation through a direct interaction. Alternatively, ER stress activates the IRE1/JNK pathway that may alter the activity of BCL-2 at the ER membrane. BI-1 is also located at the ER membrane, where it regulates calcium homeostasis.
CONCLUSIONS AND THERAPEUTIC PERSPECTIVES
I have summarized different pieces of evidence suggesting that the BCL-2 family of proteins has evolved to regulate multiple processes involved in cell survival under stress conditions. The global view of the current state of the field indicates that the BCL-2–related proteins are not only the “death gateway” keeper (as upstream regulators of caspases), but they also have multiple functions in essential processes for the cell. BCL-2–related proteins are particularly important in the physiologic maintenance of the ER, where they operate as
(a) a calcium rheostat,
(b) modulators of the UPR,
(c) regulators of ER network structure, and
(d) regulators of autophagy.
In addition, examples of a role of the BCL-2 family of proteins in cell-cycle regulation (87, 113), DNA damage responses (37, 114), and glucose/energy metabolism (16) are available, strongly supporting the notion that the BCL-2 protein family is a multifunctional group of proteins that, under normal conditions, participate in essential cellular process. In doing so, the BCL-2 protein family may represent specialized stress sentinels that actively participate in essential processes, allowing a constant homeostatic “quality control.” In response to irreversible cellular damage, particular BCL-2 family members may turn into direct activators of apoptosis.
Mutations in specific genes are responsible for a variety of neurologic disorders due to the misfolding and accumulation of abnormal protein aggregates in the brain. In many of these diseases, it has been suggested that alteration in the homeostasis of the ER contributes significantly to neuronal dysfunction.
These diseases include Parkinson’s disease (32, 84), Alzheimer’s disease (22), prion diseases (27, 28, 31), amyotrophic lateral sclerosis (ALS) (97), Huntington’s disease (63, 90) and many others (see list of diseases in 86). Consequently, the first steps in the death pathways downstream of ER stress represent important therapeutic targets. In this line of thinking, pharmacologic manipulation of the activity of the BCL-2 protein family may have beneficial consequences to treat these fatal diseases. Different small molecules and synthetic peptides are currently available with proven therapeutic applications in mouse disease models, including BCL-2 inhibitors (71), BAX channel inhibitors (29), BAX/BAK activator peptides (100, 101) and many others (see reviews in 52, 79). These drugs may be used as pharmacologic tools to manipulate the activity of stress-signaling pathways regulated by the BCL-2 protein family (i.e., autophagy, calcium metabolism, or the UPR) and their possible role in pathologic conditions.
SOURCE
Claudio A. Hetz.Antioxidants & Redox Signaling.Dec 2007.
This article represents the FRONTIER on Cardiac Regeneration as developed by Anthony Rosenzweig in Science 338, 1549 (2012).
Point #1: Current Pharmacotherapy for Cardiovascular Diseases and Heart Failure
Point #2: Dynamic model for the Adult heart capacity for cardiomyogenesis to compensate for losses occurring in heart failure: recognition of even limited regenerative capacity in the heart
Point #3: Results of Multiple Cell Therapy Clinical Trials
Point #4: The Endogenous Regeneration Potential
Point #5: On pathways regulating cardiomyocyte regeneration in animal models
Point #6: Prof. A. Rosenzweig’s Summary and His Future Outlook of Cardiac Regeneration
This article represents a continuation of the following articles on this topic that were published in this Open Access Online Scientific Journal:
Bernstein HL and A. Lev-Ari 1/14/2014 Circulating Endothelial Progenitors Cells (cEPCs) as Biomarkers
Lev-Ari, A. 11/13/2012 Peroxisome proliferator-activated receptor (PPAR-gamma) Receptors Activation: PPARγ transrepression for Angiogenesis in Cardiovascular Disease and PPARγ transactivation for Treatment of Diabetes
Lev-Ari, A. 8/29/2012 Positioning a Therapeutic Concept for Endogenous Augmentation of cEPCs — Therapeutic Indications for Macrovascular Disease: Coronary, Cerebrovascular and Peripheral
Lev-Ari, A. 8/28/2012 Cardiovascular Outcomes: Function of circulating Endothelial Progenitor Cells (cEPCs): Exploring Pharmaco-therapy targeted at Endogenous Augmentation of cEPCs
Lev-Ari, A. 8/27/2012 Endothelial Dysfunction, Diminished Availability of cEPCs, Increasing CVD Risk for Macrovascular Disease – Therapeutic Potential of cEPCs
Lev-Ari, A. 8/24/2012 Vascular Medicine and Biology: CLASSIFICATION OF FAST ACTING THERAPY FOR PATIENTS AT HIGH RISK FOR MACROVASCULAR EVENTS Macrovascular Disease – Therapeutic Potential of cEPCs
Lev-Ari, A. 7/19/2012 Cardiovascular Disease (CVD) and the Role of agent alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production
This article represent the FRONTIER on Cardiac Regeneration as developed by Anthony Rosenzweig in Science 338, 1549 (2012).
Prof. A. Rosenzweig is with the Cardiovascular Division at Beth Israel Deaconess Medical Center, Harvard Medical School, and the Harvard Stem Cell Institute, Boston, MA 02215, USA. E-mail: arosenzw@bidmc.harvard.edu
In the United States, heart failure afflicts about 6 million people (1), costs $34.4 billion each year (2), and is now the single most common discharge diagnosis in those over 65 (3). Although enormous progress has been made in managing acute cardiovascular illnesses such as heart attacks, many patients go on to develop late sequelae of their disease, including heart failure and arrhythmia. Thus, the growing number of these patients in some ways represents a burden of our success. It also reflects the incomplete success of most current therapies, which mitigate and manage but do not cure the disease.
Point #1: Current Pharmacotherapy for Cardiovascular Diseases and Heart Failure include:
Beta-blockers
Angiotensin-converting enzyme inhibitors, and
Mineralocorticoid antagonists – in congestive heart failure, they are used in addition to other drugs for additive diuretic effect, which reduces edema and the cardiac workload, and Potassium-sparing diuretics are diuretic drugs that do not promote the secretion of potassium into the urine
These medicines block pathways that are likely compensatory initially but become progressively more maladaptive, thus, prognosis and quality of life remain poor for many heart failure patients.
Point #2: Dynamic model for the Adult heart capacity for cardiomyogenesis to compensate for losses occurring in heart failure: recognition of even limited regenerative capacity in the heart
The heart has some endogenous regenerative potential
New cardiomyocytes may arise from existing cardiomyocytes and from
Progenitor or stem cells
Point #3: Results of Multiple Cell Therapy Clinical Trials
the largest randomized trial thus far— the REPAIR-AMI trial which delivered unfractionated bone marrow cells (BMCs) to patients after a heart attack—as well as
a recent meta-analysis of 50 similar trials enrolling 2625 patients (16) suggest that adverse clinical events may actually be less common in BMC-treated patients
Autologous BMCs are by far the most common cells used to date but have yielded mixed results. Two recent trials report results with heart-derived donor cells are summariezed, below. Although both of these studies break new conceptual ground, it is still too early to know how these approaches will hold up in larger studies or impactclinical outcomes, and whether heart-derived cells will have demonstrable advantages over other cell types.
1. The SCIPIO trial targeted patients with cardiac dysfunction undergoing bypass surgery for subsequent delivery of c-kit–positive cells derived from heart tissue harvested at surgery. In interim analyses, cardiac function was substantially better at 4 months in the 14 cell-treated patients available for comparison to seven control patients.
2. In CADUCEUS, autologous cells derived from cardiospheres grown from cardiac biopsies (CDCs) were delivered to patients randomized after myocardial infarction to receive CDCs or usual care. In this trial, although overall heart function was not significantly improved by cell treatment, scar (determined by magnetic resonance imaging) was reduced at 6 and 12 months in the 17 CDC-treated patients but unchanged in the eight control patients.
Point #4: The Endogenous Regeneration Potential
Donor cells have often been selected for their apparent ability to form new cardiomyocytes, the limited clinical data available suggest that relatively few of the donor cells may remain in the heart (20).
Other benefits of the cells or molecules delivered with them could include enhanced angiogenesis, cardiomyocyte survival, or endogenous regeneration.
The success or failure of cardiovascular cell therapy will ultimately depend on its ability to improve clinical outcomes whatever the mechanisms, and advocates argue that
the donor cells may provide a particularly potent mixture of salutary effects. However,
the complex and sometimes heterogeneous cell preparations being infused make standardization and reconciling discrepant results particularly challenging. It seems likely that
identification and purification of the essential cellular and molecular components mediating any observed benefits will ultimately provide the most effective, safe, and consistent approach.
Point #5: On pathways regulating cardiomyocyte regeneration in animal models
Recent work has begun to elucidate the settings and pathways regulating cardiomyocyte regeneration in animal models. Porrello et al. demonstrated a remarkable though transient regenerative capacity of the neonatal murine heart (14), and
related studies have begun to define the signaling mechanisms leading to withdrawal of cardiomyocytes from the cell cycle (21).
The Hippo pathway is a potent negative regulator of Wnt signaling and cardiomyocyte proliferation (22), which also intersects via Yap with insulin growth factor I (IGF-I) signaling (23).
How effectively these pathways can be coopted to promote regeneration after injury is of great interest.
Individual pathways may also have multiple effects.
Huang et al. ( 24) demonstrate that C/EBP inhibition, previously implicated in exercise-induced cardiac growth and possible cardiomyogenesis (25), also reduces ischemic injury by mitigating inflammation. In addition to
Endogenous pathways, reprogramming resident nonprogenitor cells such as fibroblasts through gene delivery has generated contractile cardiomyocyte-like cells (26, 27) that mitigate scar formation and improve function after heart attacks in mice (28).
These promising developments have yet to be translated clinically but could provide a path to cardiac repair that obviates the need for exogenous cells.
Point #6: Prof. A. Rosenzweig’s Summary and His Future Outlook of Cardiac Regeneration
We are still relatively early in the development of new approaches to cardiovascular disease. It will be some time before we know the conclusion of what will likely be a long and challenging road ahead.
Almost as challenging is conveying to patients and policymakers an appropriate perspective that balances unmitigated enthusiasm for the scientific discoveries, cautious optimism for the broader implications, and humble acknowledgment that though even the most appealing ideas may fail, there is only one way to find out.
Summary of Genomics and Medicine: Role in Cardiovascular Diseases
Author: Larry H. Bernstein, MD, FCAP
The articles within Chapters and Subchapters you have just read have been organized into four interconnected parts.
Genomics and Medicine
Epigenetics – Modifyable Factors Causing CVD
Determinants of CVD – Genetics, Heredity and Genomics Discoveries
Individualized Medicine Guided by Genetics and Genomics Discoveries
The first part established the
rapidly evolving science of genomics
aided by analytical and computational tools for the identification of nucleotide substitutions, or combinations of them
that have a significant association with the development of
cardiovascular diseases,
hypercoagulable state,
atherosclerosis,
microvascular disease,
endothelial disruption, and
type-2DM, to name a few.
These may well be associated with increased risk for stroke and/or peripheral vascular disease in some cases,
essentially because the involvement of the circulation is systemic in nature.
Part 1
establishes an important connection between RNA and disease expression. This development has led to
the necessity of a patient-centric approach to patient-care.
When I entered medical school, it was eight years after Watson and Crick proposed the double helix. It was also
the height of a series of discoveries elucidating key metabolic pathways.
In the period since then there have been treatments for some of the important well established metabolic diseases of
carbohydrate,
protein, and
lipid metabolism,
such as – glycogen storage disease, and some are immense challenges, such as
Tay Sachs, or
Transthyretin-Associated amyloidosis.
But we have crossed a line delineating classical Mendelian genetics to
multifactorial non-linear traits of great complexity and
involving combinatorial program analyses to resolve.
The Human Genome Project was completed in 2001, and it has opened the floodgates of genomic discovery. This resulted in the identification of
genomic alterations in
cardiovascular disease,
cancer,
microbial,
plant,
prion, and
metabolic diseases.
This has also led to
the identification of genomic targets
that are either involved in transcription or
are involved with cellular control mechanisms for targeted pharmaceutical development.
In addition, there is great pressure on the science of laboratory analytics to
codevelop with new drugs,
biomarkers that are indicators of toxicity or
of drug effectiveness.
I have not mentioned the dark matter of the genome. It has been substantially reduced, and has been termed dark because
this portion of the genome is not identified in transcription of proteins.
However, it has become a lightning rod to ongoing genomic investigation because of
an essential role in the regulation of nuclear and cytoplasmic activities.
Changes in the three dimensional structure of these genes due to
changes in Van der Waal forces and internucleotide distances lead to
conformational changes that could have an effect on cell activity.
Part 2
is an exploration of epigenetics in cardiovascular diseases. Epigenetics is
the post-genomic modification of genetic expression
by the substitution of nucleotides or by the attachment of carbohydrate residues, or
by alterations in the hydrophobic forces between sequences that weaken or strengthen their expression.
This could operate in a manner similar to the conformational changes just described. These changes
may be modifiable, and they
may be highly influenced by environmental factors, such as
smoking and environmental toxins,
diet,
physical activity, and
neutraceuticals.
While neutraceuticals is a black box industry that evolved from
the extraction of ancient herbal remedies of agricultural derivation (which could be extended to digitalis and Foxglove; or to coumadin; and to penecillin, and to other drugs that are not neutraceuticals).
The best examples are the importance of
n-3 fatty acids, and
fiber
dietary sulfur (in the source of methionine), folic acid, vitamin B12
arginine combined with citrulline to drive eNOS
and of iodine, which can’t be understated.
In addition, meat consumption involves the intake of fat that contains
the proinflammatory n-6 fatty acid.
The importance of the ratio of n-3/n-6 fatty acidsin diet is not seriously discussed when
we look at the association of fat intake and disease etiology.
Part 2 then leads into signaling pathways and proteomics.The signaling pathways are
critical to understanding the inflammatory process, just as
dietary factors tie in with a balance that is maintained by dietary intake,
possibly gut bacteria utilization of delivered substrate, and
proinflammatory factors in disaease.
These are being explored by microfluidic proteomic and metabolomic technologies that were inconceivable a half century ago.
This portion extended into the diagnosis of cardiovascular disease, and
elucidated the relationship between platelet-endothelial interaction in the formation of vascular plaque.
It explored protein, proteomic, and genomic markers
for identifying and classifying types of disease pathobiology, and
for following treatment measures.
Part 3
connected with genetics and genomic discoveries in cardiovascular diseases.
Part 4
is the tie between life style habits and disease etiology, going forward with
the pursuit of cardiovascular disease prevention.
The presentation of walking and running, and of bariatric surgery (type 2DM) are fine examples.
It further discussed gene therapy and congenital heart disease. But the most interesting presentations are
in the pharmacogenomics for cardiovascular diseases, with
volyage-gated calcium-channels, and
ApoE in the statin response.
This volume is a splendid example representative of the entire collection on cardiovascular diseases.
Introduction to Genomics and Epigenomics Roles in Cardiovascular Diseases
Author and Curator: Larry H Bernstein, MD, FCAP
This introduction is to a thorough evaluation of a rich source of research literature on the genomic influences, which may have variable strength in the biological causation of atherosclerosis, microvascular disease, plaque formation, not necessarily having expressing, except in a multivariable context that includes the environment, dietary factors, level of emotional stress, sleep habits, and the daily activities of living for affected individuals. The potential of genomics is carried in the DNA, copied to RNA, and this is most well studied in the micro RNAs (miRNA). The miRNA has been explored for the appearance in the circulation of specific miRNAs that might be associated with myocyte or endothelial cell injury, and they are also being used as targets for therapeutics by the creation of silencing RNAs (siRNA). The extent to which there is evidence of success in these studies is limited, but is being translated from animal studies to human disease. There is also a long history of the measurement of circulating enzymes and isoenzymes (alanine amino transferase, creatine kinase, and lactate dehydrogenase, not to leave out the adenylate kinase species specific to myocardium), and more recently the release of troponins I and T, and the so far still not fully explored ischemia modified albumin, or of miRNAs for the diagnosis of myocardial infarction.
There is also a significant disagreement about the value of measuring high sensitivity C reactive protein (hs-CRP), which has always been a marker for systemic inflammatory disease, in both chronic rheumatic and infectious diseases having a broad range, so that procalcitonin has appeared to be better for that situation, and for early diagnosis of sepsis. The hs-CRP has been too easily ignored because of
1. the ubiquitous elevations in the population
2. the expressed concerns that one might not be inclined to treat a mild elevation without other risk factors, such as, LDL cholesterolemia, low HDL, absent diabetes or obesity. Nevertheless, hs-CRP raises an reasonable argument for preventive measures, and perhaps the use of a statin.
There has been a substantial amount of work on the relationship of obesity to both type 2 diabetes mellitus (T2DM) and to coronary vascular disease and stroke. Here we bring in the relationship of the vascular endothelium, adipose tissue secretion of adiponectin, and platelet activation. A whole generation of antiplatelet drugs addresses the mechanism of platelet activation, adhession, and interaction with endothelium. Very interesting work has appeared on RESISTIN, that could bear some fruit in the treatment of both obesity and T2DM.
It is important to keep in mind that epigenomic gene rearrangements or substitutions occur throughout life, and they may have an expression late in life. Some of the known epigenetic events occur with some frequency, but the associations are extremely difficult to pin down, as well as the strength of the association. In a population that is not diverse, epigenetic changes are passed on in the population in the period of childbearing age. The establishment of an epigenetic change is diluted in a diverse population. There have been a number of studies with different findings of association between cardiovascular disease and genetic mutations in the Han and also in the Uyger Chinese populations, which are distinctly different populations that is not part of this discussion.
This should be sufficient to elicit broad appeal in reading this volume on cardiovascular diseases, and perhaps the entire series. Below is a diagram of this volume in the series.
PART 1 – Genomics and Medicine
Introduction to Genomics and Medicine (Vol 3)
Genomics and Medicine: The Physician’s View
Ribozymes and RNA Machines
Genomics and Medicine: Genomics to CVD Diagnoses
Establishing a Patient-Centric View of Genomic Data
VIDEO: Implementing Biomarker Programs P Ridker
PART 2 – Epigenetics – Modifiable
Factors Causing CVD
Diseases Etiology
Environmental Contributors
Implicated as Causing CVD
Diet: Solids and Fluid Intake
and Nutraceuticals
Physical Activity and
Prevention of CVD
Psychological Stress and
Mental Health: Risk for CVD
Correlation between
Cancer and CVD
PART 3 Determinants of CVD – Genetics, Heredity and Genomics Discoveries
Introduction
Why cancer cells contain abnormal numbers of chromosomes (Aneuploidy)
Functional Characterization of CV Genomics: Disease Case Studies @ 2013 ASHG
Leading DIAGNOSES of CVD covered in Circulation: CV Genetics, 3/2010 – 3/2013
Commentary on Biomarkers for Genetics and Genomics of CVD
PART 4 Individualized Medicine Guided by Genetics and Genomics Discoveries
Medical Etiologies: EBM – LEADING DIAGNOSES, Risks
Pharmacogenomics for Cardio-
vascular Diseases
Signaling Pathways
Response to Rosuvastatin in
Patients With Acute Myocardial Infarction:
Hepatic Metabolism and Transporter Gene
Variants Effect http://pharmaceuticalintelligence.com/2014/
01/02/response-to-rosuvastatin-in-patients-
with-acute-myocardial-infarction-hepatic-
metabolism-and-transporter-gene-variants-effect/
Proteomics and Metabolomics
Voltage-Gated Calcium Channel and Pharmaco-
genetic Association with Adverse Cardiovascular
Outcomes: Hypertension Treatment with Verapamil
SR (CCB) vs Atenolol (BB) or Trandolapril (ACE) http://pharmaceuticalintelligence.com/2014/01/02/
voltage-gated-calcium-channel-and-pharmacogenetic-
association-with-adverse-cardiovascular-outcomes-
hypertension-treatment-with-verapamil-sr-ccb-vs-
atenolol-bb-or-trandolapril-ace/
Genomics has had a rapid growth of research into variability of human genetics in both healthy populations in the study of population migration, and in the study of genetic sequence alterations that may increase the risk of expressed human disease. This is the case for cardiology, cancer, inflammtory conditions, and gastrointestinal diseases. For the most part, genomics research in the last decade has shed light on potential therapeutic targets, but the identification of drug toxicities in late phase trials has been associated with a 70 percent failure rate in bringing new drugs to the market. Despite good technologies for investigative studies, initial work is carried out on animals and then the transferrability of the work from a “model” to man has to be assured. That is the first issue of concern.
Secondly, there is a well considered reluctance on the part of experienced and well prepared physicians to be “early” adopters to newly introduced drugs, with the apprehension that unidentified clinical problems can be expected to be unmasked. It is, however, easier to consider when a new drug belongs to an established class of medications, and it has removed known adverse effects. In this case, the adverse effects are known side effects, but not necessarily serious drug reactions that would preclude use.
A third consideration is the cost of drug development, and the cost of development is passed on to the healthcare organization in the purchasing cost. We can rest assured that the Pharmacy and Therapeutics Review Committee will not cease meeting on a regular schedule anytime soon. Further, how do the drug failures become embedded in the cost of the pharmaceutical budget passed on to the recipient. Historically, insurance is an actuarial discipline. But in the lifetime of an individual, they are bound to see a physician for acute or chronic medical attention. Only the timing cannot be predicted. As a result, dealing with the valid introduction of new medications is a big concern for both the public and the private insurer.
How does this compute for the physician provider. The practice of medicine is not quickly adaptive, as the physician’s primary concern is to do no harm. Genomics testing is not widely available, and it is for the most part not definitive for diagnostic purposes as things stand today. It may provide assessment of risk, or of survival expectation. The physician uses a step by step assessment, using the patient and family history, a focused physical exam, laboratory and radiology, proceeding to other more specialized exams. Much of the laboratory testing is based on the appearance in the circulation of changes in blood chemistry of the nature of electrolytes, circulating cells in the blood and of the blood forming organ, proteins, urea and uric acid. They are not exquisitely sensitive, but they might be sufficient for their abnormal concentrations appearing at the time the patient presents with a complaint. What tests are ordered is determioned by a need for relevant information to make a medical decision.
The relevant questions are:
1. acuity of symptoms and signs. 2. actions to be taken. 3. tests that are needed to clarify the examination findings.
once a provisional diagnosis is obtained, referrals, additional testing, and medication orders are provided based on the assessment.
Where does genetic testing fit into this? At this point, it will only be used
to confirm a restricted list of diagnoses that have a high association with the condition, and
only with the participation of a medical geneticist, when
profiling the patient and other members of the family is required.
Curation, HealthCare System in the US, and Calcium Signaling Effects on Cardiac Contraction, Heart Failure, and Atrial Fibrillation, and the Relationship of Calcium Release at the Myoneural Junction to Beta Adrenergic Release
Curator and e-book Contributor: Larry H. Bernstein, MD, FCAP
Curator and BioMedicine e-Series Editor-in-Chief: Aviva Lev Ari, PhD, RN
This portion summarises what we have covered and is now familiar to the reader. There are three related topics, and an extension of this embraces other volumes and chapters before and after this reading. This approach to the document has advantages over the multiple authored textbooks that are and have been pervasive as a result of the traditional publication technology. It has been stated by the founder of ScoopIt, that amount of time involved is considerably less than required for the original publications used, but the organization and construction is a separate creative process. In these curations we amassed on average five articles in one curation, to which, two or three curators contributed their views. There were surprises, and there were unfulfilled answers along the way. The greatest problem that is being envisioned is the building a vision that bridges and unmasks the hidden “dark matter” between the now declared “OMICS”, to get a more real perspective on what is conjecture and what is actionable. This is in some respects unavoidable because the genome is an alphabet that is matched to the mino acid sequences of proteins, which themselves are three dimensional drivers of sequences of metabolic reactions that can be altered by the accumulation of substrates in critical placements, and in addition, the proteome has functional proteins whose activity is a regulatory function and not easily identified. In the end, we have to have a practical conception, recognizing the breadth of evolutionary change, and make sense of what we have, while searching for more.
We introduced the content as follows:
1. We introduce the concept of curation in the digital context, and it’s application to medicine and related scientific discovery.
Topics were chosen were used to illustrate this process in the form of a pattern, which is mostly curation, but is significantly creative, as it emerges in the context of this e-book.
Alternative solutions in Treatment of Heart Failure (HF), medical devices, biomarkers and agent efficacy is handled all in one chapter.
PCI for valves vs Open heart Valve replacement
PDA and Complications of Surgery — only curation could create the picture of this unique combination of debate, as exemplified of Endarterectomy (CEA) vs Stenting the Carotid Artery (CAS), ischemic leg, renal artery stenosis.
2. The etiology, or causes, of cardiovascular diseases consist of mechanistic explanations for dysfunction relating to the heart or vascular system. Every one of a long list of abnormalities has a path that explains the deviation from normal. With the completion of the analysis of the human genome, in principle all of the genetic basis for function and dysfunction are delineated. While all genes are identified, and the genes code for all the gene products that constitute body functions, there remains more unknown than known.
3. Human genome, and in combination with improved imaging methods, genomics offers great promise in changing the course of disease and aging.
4. If we tie together Part 1 and Part 2, there is ample room for considering clinical outcomes based on individual and organizational factors for best performance. This can really only be realized with considerable improvement in information infrastructure, which has miles to go.
Curation
Curation is an active filtering of the web’s and peer reviewed literature found by such means – immense amount of relevant and irrelevant content. As a result content may be disruptive. However, in doing good curation, one does more than simply assign value by presentation of creative work in any category. Great curators comment and share experience across content, authors and themes.
Great curators may see patterns others don’t, or may challenge or debate complex and apparently conflicting points of view. Answers to specifically focused questions comes from the hard work of many in laboratory settings creatively establishing answers to definitive questions, each a part of the larger knowledge-base of reference. There are those rare “Einstein’s” who imagine a whole universe, unlike the three blindmen of the Sufi tale. One held the tail, the other the trunk, the other the ear, and they all said this is an elephant!
In my reading, I learn that the optimal ratio of curation to creation may be as high as 90% curation to 10% creation. Creating content is expensive. Curation, by comparison, is much less expensive. The same source says “Scoop.it is my content marketing testing “sandbox”. In sharing, he says that comments provide the framework for what and how content is shared.
Healthcare and Affordable Care Act
We enter year 2014 with the Affordable Care Act off to a slow start because of the implementation of the internet signup requiring a major repair, which is, unfortunately, as expected for such as complex job across the US, and with many states unwilling to participate. But several states – California, Connecticut, and Kentucky – had very effective state designed signups, separate from the federal system. There has been a very large rush and an extension to sign up. There are many features that we can take note of:
1. The healthcare system needed changes because we have the most costly system, are endowed with advanced technology, and we have inexcusable outcomes in several domains of care, including, infant mortality, and prenatal care – but not in cardiology.
2. These changes that are notable are:
The disparities in outcome are magnified by a large disparity in highest to lowest income bracket.
This is also reflected in educational status, and which plays out in childhood school lunches, and is also affected by larger class size and cutbacks in school programs.
This is not helped by a large paralysis in the two party political system and the three legs of government unable to deal with work and distraction.
Unemployment is high, and the banking and home construction, home buying, and rental are in realignment, but interest rates are problematic.
3. The medical care system is affected by the issues above, but the complexity is not to be discounted.
The medical schools are unable at this time to provide the influx of new physicians needed, so we depend on a major influx of physicians from other countries
The technology for laboratories, proteomic and genomic as well as applied medical research is rejuvenating the practice in cardiology more rapidly than any other field.
In fields that are imaging related the life cycle of instruments is shorter than the actual lifetime use of the instruments, which introduces a shortening of ROI.
Hospitals are consolidating into large consortia in order to maintain a more viable system for referral of specialty cases, and also is centralizing all terms of business related to billing.
There is reduction in independent physician practices that are being incorporated into the hospital enterprise with Part B billing under the Physician Organization – as in Partners in Greater Boston, with the exception of “concierge” medical practices.
There is consolidation of specialty laboratory services within state, with only the most specialized testing going out of state (Quest, LabCorp, etc.)
Medicaid is expanded substantially under the new ACA.
The federal government as provider of services is reducing the number of contractors for – medical devices, diabetes self-testing, etc.
The current rearrangements seeks to provide a balance between capital expenses and fixed labor costs that it can control, reduce variable costs (reagents, pharmaceutical), and to take in more patients with less delay and better performance – defined by outside agencies.
Cardiology, Genomics, and calcium ion signaling and ion-channels in cardiomyocyte function in health and disease – including heart failure, rhythm abnormalities, and the myoneural release of neurotransmitter at the vesicle junction.
This portion is outlined as follows:
2.1 Human Genome: Congenital Etiological Sources of Cardiovascular Disease
2.2 The Role of Calcium in Health and Disease
2.3 Vasculature and Myocardium: Diagnosing the Conditions of Disease
Genomics & Genetics of Cardiovascular Disease Diagnoses
disruption of Ca2+ homeostasis cardiac & vascular smooth muscle
synaptotagmin as Ca2+ sensor & vesicles
atherosclerosis & ion channels
It is increasingly clear that there are mutations that underlie many human diseases, and this is true of the cardiovascular system. The mutations are mistakes in the insertion of a purine nucleotide, which may or may not have any consequence. This is why the associations that are being discovered in research require careful validation, and even require demonstration in “models” before pursuing the design of pharmacological “target therapy”. The genomics in cardiovascular disease involves very serious congenital disorders that are asserted early in life, but the effects of and development of atherosclerosis involving large and medium size arteries has a slow progression and is not dominated by genomic expression. This is characterized by loss of arterial elasticity. In addition there is the development of heart failure, which involves the cardiomyocyte specifically. The emergence of regenerative medical interventions, based on pleuripotent inducible stem cell therapy is developing rapidly as an intervention in this sector.
Finally, it is incumbent on me to call attention to the huge contribution that research on calcium (Ca2+) signaling has made toward the understanding of cardiac contraction and to the maintenance of the heart rhythm. The heart is a syncytium, different than skeletal and smooth muscle, and the innervation is by the vagus nerve, which has terminal endings at vesicles which discharge at the myocyte junction. The heart specifically has calmodulin kinase CaMK II, and it has been established that calmodulin is involved in the calcium spark that triggers contraction. That is only part of the story. Ion transport occurs into or out of the cell, the latter termed exostosis. Exostosis involves CaMK II and pyruvate kinase (PKC), and they have independent roles. This also involves K+-Na+-ATPase. The cytoskeleton is also discussed, but the role of aquaporin in water transport appears elsewhere, as the transport of water between cells. When we consider the Gibbs-Donnan equilibrium, which precedes the current work by a century, we recall that there is an essential balance between extracellular Na+ + Ca2+ and the intracellular K+ + Mg2+, and this has been superceded by an incompletely defined relationship between ions that are cytoplasmic and those that are mitochondrial. The glass is half full!
The amount of success in stem cell research and recent successes is notable.
GEN News Dec 5, 2013
Stem Cell Leaders Call for Human Embryome Project
Just as an international consortium was formed to map and sequence the human genome, now a group of stem cell and regenerative medicine scientists say it’s critical that such an effort be ramped up to do a similar project focused on the human embryome.
This was the key message of a panel discussion, “From Mapping the Genome to Mapping the Embryome: The Urgent Need for an International Initiative,” moderated by Michael West, Ph.D., CEO of Biotime. It took place at the World Stem Cell Summit, which is taking place this week in San Diego.
“It is becoming increasingly clear in regenerative medicine that pluripotent stem cells, embryonic stem cells, and IPs cells will be as fundamentally important to medicine as was DNA. Maybe even bigger because you can genetically engineer these cells,” said Dr. West.
Dr. West and his colleagues adamantly believe that there needs to be a large international effort aimed at mapping the cellular and molecular basis of all human life starting with the fertilized egg and working its way up to the body of the adult. This is what it is termed the embryome.
“The opportunity presented by pluripotent stem cells to manufacture for the first time in the history of medicine all of the cellular components of the human body on an industrial scale is at once both an opportunity and a challenge,” said Dr. West. “The opportunity is to build a new field we call regenerative medicine in which many currently incurable diseases are treated with cells capable of regenerating tissues afflicted with disease. The challenge relates to the complexity of the cell types in the body and our ability to manufacture products with precisely defined compositions for human clinical use.”
Dr. West went on to say that to get these different types of stem cells into the clinic, and approved by the FDA, researchers will fully need to understand all aspects of the biology of these cells. An identification and understanding of any contaminating cells will also be essential to success in this field. The question to ask is “What is in the syringe?”
Unlike recombinant DNA, continued Dr. West, the contaminants in pluripotent stem cells are alive and may make things that are undesirable at the intended point of therapy. For example, you might have a bioreactor full of cells that are making heart muscle to regenerate heart function in a patient. But you have to be careful that your cells are not contaminated with neural crest cells from the head area which could generate a tooth along with the heart muscle.
“These contaminants, if you do not remove them, can lead to years of delay in filing an IND and a runup in costs as you try to identify these cells,” explained Dr. West.
The major problem in identifying them, according to Dr. West, is that no one has ever mapped the molecular markers or even a rudimentary cell ontology tree, i.e., mapped out the tree from the fertilized egg to the cells of the human body.
“If [there were] a detailed map of all the cellular and molecular components of life from the fertilized egg to adulthood, and then databased in a manner to the information in the human genome, medicine would be the true beneficiary,” added Dr. West. “That’s why we have made this call for an international initiative.”
Also, watch our video “A Brief History of Stem Cells” to see a timeline spanning over 60 years of stem cell research.
Mary Ann Liebert Wins Stem Cell Education Award
Mary Ann Liebert, president and CEO of Mary Ann Liebert Inc., and publisher of GEN, was presented with the Stem Cell Education Award by the Genetics Policy Institute. The award was given during a ceremony at dinner which took place at the World Stem Cell Summit, which is being held in San Diego this week.
Liebert was cited for her outstanding “work in educating patients, researchers, and the broader stem cell community, and in raising the standard in medical research journalism.” Among the seventy journals the Liebert company publishes is the peer-reviewed Stem Cells and Development.
In her acceptance speech Liebert told the audience that she was extremely gratified in being so recognized and thanked the entire staff at her company for their dedication in helping to promote excellence in medical publishing.
In his introductory remarks during the award ceremony GEN’s long-time editor in chief John Sterling noted that Mary Ann always encourages her editors and writers “to inform, enlighten when they can, and educate as much as possible.”
Sterling added that while she started her company 33 years ago her vision for her publications remains the same: “to help advance our knowledge of science and medicine in the best ways possible.”
Neural Precursors “Cure MS” in Mice
During a session at the this week’s World Stem Cell Summit in San Diego, an international research team described an “astonishing” experiment in which a mouse model of multiple sclerosis was able to virtually totally recover and move normally after being transplanted with human neural precursor cells (hNPC). The scientists were able to show almost full recovery in the mice up to six months later.
The investigators, led by Jeanne Loring, Ph.D., from the Scripps Research Institute, included scientists from the University of California, Irvine and a group from Australia.
“Our goal was to demonstrate cell therapy for MS,” Dr. Loring told the audience.
According to Ronald Coleman, a graduate student working with Dr. Loring and who is at UC-Irvine, the team used mice infected with a neurotropic JHM variant of mouse hepatitis virus (JHMV) as a model for MS. They injected hNPCs derived from human pluripotent stem cells (hPSC) into the mice to explore treatment options for the disease.
The results were indeed astonishing, said Dr. Loring. Non-control mice were able to move about in a manner that can be described as consistent and long lasting. T-cell proliferation was reduced and T regulatory cell induction took place. The spinal cords of the mice not only did not undergo further demyelination but actually exhibited remyelination. The control mice dragged their legs around when they tried to move.
“The only problem was that the hNPCs themselves are not directly responsible for the cure. They are not even there when the mice start walking,” explained Dr. Loring. “Those cells are rejected after seven days and we start to see a therapeutic response in three weeks.”
Both Dr. Loring and Coleman believe that the hNPCs are secreting proteins, like cytokines, that do the actual repair work in the CNS of the mice.
“We identified a set of candidate proteins secreted by hNPCs and not by undifferentiated pluripotent stem cells,” continued Dr. Loring, who said the team plans to continue building on this initial research.
World Stem Cell Summit: December 4, 2013 Update
GEN is on the scene at the World Stem Cell Summit in San Diego. Here are some highlights from the conference so far:
Bernard Siegel, J.D., founder and co-chair of the World Stem Cell Summit (WSCS) and executive director of Genetics Policy Institute, today welcomed attendees of WSCS 2013, being held December 4–6, in San Diego, CA.
“Stem cell science represents, to those afflicted with chronic disease, a vehicle for modeling disease and therapeutic development,” states Siegel in World Stem Cell Report 2013, a supplement to Stem Cells and Development (2013;22;Suppl1). “The field is a true scientific revolution and reflects the transformative power of hope, a powerful engine for progress.”
“The future is here now,” says Mahendra Rao, M.D., Ph.D., director, NIH Center for Regenerative Medicine, who delivered a plenary keynote and moderated the plenary panel discussion, “How Stem Cells are Transforming Medicine.” Cell therapies have been used to treat people safely and effectively; the technical barriers have been addressed. The challenge now is to reduce the cost of manufacturing. To drive routine adoption of cell therapy it must be cost effective and must demonstrate more than incremental benefit, according to Dr. Rao.
Professor Teruo Okano, Ph.D., Tokyo Women’s Medical University, described his group’s Cell Sheet Tissue Engineering strategy that involves enzymatic membrane disruption during cell harvesting and growth of an autologous cell sheet for transplantation on an “intelligent surface” that reversibly changes properties from hydrophobic to hydrophilic with a reversible in temperature from 37°C to 20°C. Dr. Okano further described the development of an automatic tissue factory and thick tissue evaluation system for fully automated, industrialized GMP cell processing.
Andre Terzic, M.D., Ph.D., Center for Regenerative Medicine, Mayo Clinic, noted during the opening session of the WSCS that “the Mayo Clinic has embraced regenerative medicine as a strategy for the future of medicine,” and he described their blueprint for moving from knowledge to delivery of treatments and procedures. Education is a critical dimension of this process. Another important component, according to Dr. Terzic, is the Regenerative Medicine Biotrust, in which “the patient is the center of the solution” to develop combinations of diagnostics and therapeutics and conduct clinical trials.
Regardless of the outcomes of current or future clinical trials, “I would argue that we have already seen breakthroughs,” said Evan Snyder, Ph.D., Sanford-Burnham Medical Research Institute, as stem cells “have completely changed the way medicine thinks about disease and development.” They have led to new views on plasticity and regeneration and the development of different types of drug targets.
WSCS 2013 is organized by the Genetics Policy Institute (GPI), California Institute for Regenerative Medicine (CIRM), Institute for Integrated Cell-Material Sciences at Kyoto University (iCeMS), Mayo Clinic, Sanford-Burnham Medical Research Institute, and The Scripps Research Institute. Mary Ann Liebert, Inc. publishers and Genetic Engineering & Biotechnology News (GEN) are sponsors of the summit.
Drug Testing Should Be with Human iPS Cells
Fri, 12/06/2013 – drug discovery & development (DDD)
Once established such neural stem cells can be used to continuously generate neurons for drug testing and disease modeling. Depicted is an immunofluorescence staining where proteins characteristic of neural stem cells are labeled with fluorescing antibodies (Nestin in green, Dach1 in red). (Source: Jerome Mertens / Uni Bonn)Once established such neural stem cells can be used to continuously generate neurons for drug testing and disease modeling. Depicted is an immunofluorescence staining where proteins characteristic of neural stem cells are labeled with fluorescing antibodies (Nestin in green, Dach1 in red). (Source: Jerome Mertens / Uni Bonn)Why do certain Alzheimer medications work in animal models but not in clinical trials in humans? A research team from the University of Bonn and the biomedical enterprise Life & Brain GmbH has been able to show that results of established test methods with animal models and cell lines used up until now can hardly be translated to the processes in the human brain. Drug testing should therefore be conducted with human nerve cells, conclude the scientists. The results are published by Cell Press in the journal Stem Cell Reports.
In the brains of Alzheimer’s patients, deposits form that consist essentially of beta-amyloid and are harmful to nerve cells. Scientists are therefore searching for pharmaceutical compounds that prevent the formation of these dangerous aggregates. In animal models, certain non-steroidal anti-inflammatory drugs (NSAIDs) were found to a reduced formation of harmful beta-amyloid variants. Yet, in subsequent clinical studies, these NSAIDs failed to elicit any beneficial effects.
“The reasons for these negative results have remained unclear for a long time”, said Oliver Brüstle, director of the Institute for Reconstructive Neurobiology of the University of Bonn and CEO of Life & Brain GmbH. “Remarkably, these compounds were never tested directly on the actual target cells—the human neuron”, added lead author Jerome Mertens of Brüstle’s team, who now works at the Laboratory of Genetics in La Jolla (USA). This is because, so far, living human neurons have been extremely difficult to obtain. However, with the recent advances in stem cell research it has become possible to derive limitless numbers of brain cells from a small skin biopsy or other adult cell types.
Scientists transform skin cells into nerve cells
Now a research team from the Institute for Reconstructive Neurobiology and the Department of Neurology of the Bonn University Medical Center together with colleagues from the Life & Brain GmbH and the University of Leuven (Belgium) has obtained such nerve cells from humans. The researchers used skin cells from two patients with a familial form of Alzheimer’s Disease to produce so-called induced pluripotent stem cells (iPS cells), by reprogramming the body’s cells into a quasi-embryonic stage. They then transformed the resulting iPS cells into nerve cells.
Using these human neurons, the scientists tested several compounds in the group of NSAIDs. As control, the researchers used nerve cells they had obtained from iPS cells of donors who did not have the disease. Both in the nerve cells obtained from the Alzheimer’s patients and in the control cells, the NSAIDs that had previously tested positive in the animal models and cell lines typically used for drug screening had practically no effect: The values for the harmful beta-amyloid variants that form the feared aggregates in the brain remained unaffected when the cells were treated with clinically relevant dosages of these compounds.
Metabolic processes in animal models differ from humans
“In order to predict the efficacy of Alzheimer drugs, such tests have to be performed directly on the affected human nerve cells”, concluded Brüstle’s colleague Philipp Koch, who led the study. Why do NSAIDs decrease the risk of aggregate formation in animal experiments and cell lines but not in human neurons? The scientists explain this with differences in metabolic processes between these different cell types. “The results are simply not transferable”, says Koch.
The scientists now hope that in the future, testing of potential drugs for the treatment of Alzheimer’s disease will be increasingly conducted using neurons obtained from iPS cells of patients. “The development of a single drug takes an average of ten years”, said Brüstle. “By using patient-specific nerve cells as a test system, investments by pharmaceutical companies and the tedious search for urgently needed Alzheimer medications could be greatly streamlined”.
Calcium Signaling, Cardiac Mitochondria and Metabolic Syndrome
Larry H Bernstein: Author
and
Reporter: Aviva Lev-Ari, PhD, RN
Mitochondria, the cardiovascular system and metabolic syndrome
Start date
April 24, 2013
End date
April 24, 2013
Venue
London, UK / Kennedy Lecture Theatre, Institute of Child Health
Location
London, UK
Topics
– Mitochondrial ROS metabolism in the heart
– Mitochondrial permeability transition pore
– Mitochondria in vascular smooth muscle
– Therapeutic targets for cardiac disease
Invited speakers
This event has now passed – please visit our Conference calendar for future Abcam events
Confirmed speakers:
Paolo Bernardi, University of Padova, Italy ‘The mitochondrial permeability transition pore: A mystery solved?’
Susan Chalmers, University of Strathclyde Glasgow ‘Mitochondria in vascular smooth muscle: from regulation of calcium signals to control of proliferation’
Andrew Hall, UCL ‘The role of sirtuin 3 in cardiac dysfunction’
Derek Hausenloy, UCL ‘Mitochondrial dynamics as a therapeutic target for cardiac disease’
Guy Rutter, Imperial College London ‘Mitochondria and insulin secretion – links to diabetes’
Michael Murphy, MRC Mitochondiral Biology Unit, Cambridge ‘Exploring mitochondrial ROS metabolism in the heart using targeted probes and bioactive molecules’
Toni Vidal Puig, Institute of Metabolic Science, University of Cambridge ‘Adipose tissue expandability, lipotoxicity and the metabolic syndrome’
Calcium signaling is instrumental for excitation-contraction coupling (ECC). The involvement of mitochondria in establishing rapid cytosolic calcium transients in this process remain debated.
Two models have emerged:
slow integration versus rapid and
ample beat-to-beat changes of
cytosolic calcium transients into the mitochondria matrix.
a brief outline of cardiac calcium signaling »
Mitochondrial Calcium transport mechanisms
Calcium influx can be mediated by:
Mitochondrial Calcium Uniporter (MCU)
Mitochondrial Ryanodine receptor type 1 (mRyR1)
Leucine-zipper-EF-hand-containing transmembrane protein 1 (LETM1)
Don’t Ignore the Many Lessons of the MitraClip Failure
John M. Mandrola, MD
August 30, 2018
Comments
It would be wrong to say that use of this device for this indication provided no benefit to patients. The more accurate conclusion is that the MitraClip caused net harm. That’s because in addition to no benefit in the efficacy endpoints, patients in the device group endured a procedural complication rate of more than 10%, including a sevenfold higher rate of stroke.
Once again, we can learn both specific lessons about the treatment of people with heart failure and more general lessons on the acceptance of untested therapeutics.
Other comments
Dr. MIGUEL QUINTANA| Cardiology, General
A bad day for interventional cardiology. I do believe that interventional cardiologist are aware about the mechanisms of severe MR in dilated hearts, however when a point of no return in those ventricles is reached, something has to be done.
I do agree with Dr. Mandrola regarding the behaviour of the industry to drive new devices in medical practice without performing RCT. However the main responsible are the institutions approving the devices (FDA and European Commission for drugs and devices).
I wish to hear some comments of Dr. Mandrola regarding the new trends in performing RCT using just the non-inferiority criteria and the growing trends of using the “big data” of mega data registries to establish guidelines for clinical treatments and not only to test new hypothesis.
Dr. James Rittelmeyer| Cardiology, Interventional
When the point of no return has been reached palliative care is a great plan. It causes no harm and is relatively inexpensive.
Dr. Johannes Schaar| Cardiology, General
Right!!!!!! We should stay away from interventional cardiologists, who have know idea what they do and are on the payroll of the industry
This link suggests that the only FDA approved device may have a more limited indication, but is still helping the very sickest patients, with the ‘negative’ outcome for the quoted study. Functional Mitral Regurgitation (6 M patients in the US) still has no approved viable transcatheter therapy, and the interpretations of the latest study results suggest a more restricted patient selection for the MitraClip®device.
Edward Hlozek, Chairman and CEO, ValveCure, LLC, on 8/30/2018
BarrelEye portends to be available to all classes of patients with Functional MR and significantly improve quality of life and extend lives, offering future non-invasive repeatability of the therapy, without an implant.
Earlier Intervention for Mitral Valve Disease May Lead to Improved Outcomes
Slow progression of disease may mask symptoms until damage cannot be fully repaired
In this study, the data showed that the overall repair rate was 65.6 percent (57,244) and the replacement rate was 34.4 percent (29,970). Overall operative mortality was 2 percent (1,762).
“We found that the number of operations performed for mitral valve disease is growing faster than any other category of heart operation and that the results were excellent with low risks of death and complications,” said Gammie.
The researchers also revealed that while the prevalence of mitral valve disease and the number of mitral valve operations performed per year are increasing, overall aortic valve operations were performed 1.6 times more commonly than mitral valve operations during the study period.
“This may suggest important under-referral and under-treatment of mitral valve disease, which may be related to the slower progression of signs and symptoms of mitral compared to aortic disease, as well as potential lack of adherence to guidelines for intervention,” said Gammie. “So although contemporary outcomes are excellent, there remains an important and substantial opportunity to improve results for patients with mitral valve disease by following established guidelines and encouraging earlier referral for operation.”
Percutaneous repair or replacement for mitral regurgitation?
by Ted E. Feldman, MD
by Nicole Lou
Contributing Writer, MedPage TodayApril 04, 2017
Mitral repair is still a relatively youthful field at 14 years, but now operators are taking it further and developing methods for mitral valve replacement, says Ted E. Feldman, MD, of Evanston Hospital in Illinois, where mitral repair first got its start.
In this exclusive MedPage Today video, the interventionist shares his insight into the limitations of the device synonymous with mitral repair, the MitraClip, and discusses the current challenges of outright percutaneous replacement of the valve.
“100 patients underwent Mitral valve repair vs 1000s of Aortic valve the TAVR.”
MV repair via transcatheter valve implant (TMVR) will be extremely difficult to get right because of the complex nature of the anatomy versus the simple circle that is the aortic valve (TAVR)…and MitraClip is limited because leaflets sometime cannot be caught right for the device to be implanted. Think of ValveCure’s platform device that is not an implant and tightens up the valve biologically.
Aortic and Pulmonic are basically planar circular shapes. The shape of the Mitral and Tricuspid are parabolic ellipsoidal. This unique shape makes designing a transcatheter mitral valve implant challenging, especially considering that most are of a unique shape and dimension. And the aortic is more calcified, which lends to a better attachment of a transcatheter implant because it is more rigid and planar.
MitraClip Issues, Outcomes Come to Fore in US Registry Experience
by Nicole Lou
Reporter, MedPage Today/CRTonline.org
10.03.2016
Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner
Cardioband is a product of Valtech acquired by Heartware in 2015. Medtronic completed acquisition of Heartware in August 2016. See Updates, below
A novel surgical-style transcatheter device showed promise for the treatment of functional mitral regurgitation, investigators reported.
The Cardioband direct annuloplasty device was associated with no periprocedural deaths and had a 1-month mortality rate of 5%, according to Georg Nickenig, MD, of Heart Center Bonn in Germany, and colleagues in their study published online in JACC: Cardiovascular Interventions. By 6 months, the death rate had climbed to 9.6%.
Annular septolateral dimensions fell from 3.7 cm at baseline to 2.5 cm at 1 month and 2.4 cm after 6 months (P<0.001) with the device, which is implanted in a transvenous, transseptal procedure to encircle the valve annulus and, secured with small anchors, cinch it until the valve closes fully again.
In addition, the proportion of patients with grade 3 or worse mitral regurgitation also dropped from 77.4% to 10.7% at 1 month (P<0.001) and was recorded at 13.6% after 6 months (P<0.001). The proportion still categorized as being in New York Heart Association functional class III or IV dropped from 95.5% at baseline to 18.2% (P<0.001).
Over the 6-month follow-up in the study, exercise capacity generally improved (332 m in a 6-minute walking test versus 250 m at baseline, P<0.001), as did patients’ quality of life (Minnesota Living With Heart Failure Questionnaire score 18.1 versus 38.2 at baseline,P<0.001).
Medtronic Completes Acquisition of HeartWare International
Broadens Heart Failure Leadership Into Growing Circulatory Support Sector
DUBLIN – Aug. 23, 2016 – Medtronic plc (NYSE: MDT), the global leader in medical technology, has completed its acquisition of HeartWare International, Inc., a leading innovator of less-invasive, miniaturized, mechanical circulatory support technologies (MCS) for treating patients with advanced heart failure. HeartWare will become part of the Heart Failure business within the Medtronic Cardiac Rhythm and Heart Failure division. Under the terms of the transaction, each outstanding share of HeartWare common stock has been converted into the right to receive $58.00 in cash, without interest, subject to any required withholding of taxes.
HeartWare develops and manufactures miniaturized implantable heart pumps, or ventricular assist devices (VAD), to treat patients around the world suffering from advanced heart failure. Its flagship product, the HVAD® System, features the world’s smallest full-support VAD and is indicated for refractory end-stage left-ventricular heart failure patients in the U.S. who are awaiting a heart transplant, as well as approved in Europe for long-term use in patients at risk of death from refractory, end-stage heart failure.
Medtronic estimates that the global VAD market is approximately $800 million currently, and worldwide is expected to grow in the mid-to-high single digits for calendar years 2016-17, and accelerate to high-single/low-double digits beyond calendar year 2017.
“Not only does the current HeartWare portfolio expand Medtronic leadership across the heart failure continuum, its product pipeline – when married with our expertise – can result in progressively less-invasive heart pumps that have the potential to benefit even more patients,” said David Steinhaus, M.D., vice president and general manager of the Heart Failure business, and medical director for the Cardiac Rhythm and Heart Failure division at Medtronic. “Today, Medtronic offers the industry’s leading cardiac resynchronization therapy devices, including MR-conditional CRT-defibrillators; MCS therapy for advanced heart failure patients; heart failure diagnostics; and meaningful expert analysis through Medtronic Care Management Services, including the recently launched Beacon Heart Failure Management Service.”
The acquisition of HeartWare broadens the Medtronic portfolio of therapies, diagnostic tools and services for patients suffering from heart failure, aligning with Medtronic’s Mission of alleviating pain, restoring health and extending life. The acquisition is part of the Company’s therapy innovation strategy to surround the physician with innovative products while focusing on patients and disease states.
“This is an exciting moment, as more than 600 HeartWare employees are now part of the broader Medtronic organization,” said Doug Godshall, who served as president and chief executive of HeartWare for the past decade. “HeartWare has delivered incredible advancements for patients suffering from heart failure, through the commercialization of the HVAD system and pipeline development, and I am convinced that being part of Medtronic will allow us to accelerate meaningful innovations even more quickly.”
Heart failure, also known as congestive heart failure, is a condition in which the heart isn’t pumping enough blood to meet the body’s needs. Heart failure usually develops slowly after an injury to the heart. Some injuries may include a progressive deterioration of the heart muscle, heart attack, untreated high blood pressure, or heart valve disease. Heart failure remains a leading cause of hospitalization and death in the United States, and its prevalence continues to increase, affecting more than 5 million people in the U.S. alone. The cost of heart failure is high. Healthcare expenditures in the U.S. on heart failure are estimated to be approximately $39 billion per year, making it one of the largest expenses to the healthcare system. With the aging of the population, Medtronic estimates that the number of patients with heart failure could exceed 8 million by 2030.
This transaction is expected to meet Medtronic’s long-term financial metrics for acquisitions. Medtronic does not intend to modify its fiscal year 2017 revenue outlook or earnings per share (EPS) guidance as a result of this transaction, although it is expected to provide increased confidence in the company’s ability to deliver on its FY17 revenue growth outlook. In addition, Medtronic expects minimal to no net EPS dilution from this transaction for the first two years as the company intends to offset the expected dilutive impact. The acquisition is expected to be earnings accretive in year three.
In collaboration with leading clinicians, researchers and scientists worldwide, Medtronic offers the broadest range of innovative medical technology for the interventional and surgical treatment of cardiovascular disease and cardiac arrhythmias. The company strives to offer products and services of the highest quality that deliver clinical and economic value to healthcare consumers and providers around the world.
The Tender Offer and Merger The tender offer for all of the outstanding shares of HeartWare common stock expired as scheduled immediately after 11:59 p.m. Eastern time on August 22, 2016. Computershare Trust Company, N.A., the depositary and paying agent for the tender offer, has advised Medtronic that 14,952,817 shares of HeartWare common stock were validly tendered and not properly withdrawn in the tender offer, representing approximately 85.15% of the outstanding shares. All of the conditions to the tender offer have been satisfied, and on August 23, 2016, Medtronic Acquisition Corp., a subsidiary of Medtronic, accepted for payment and will promptly pay for all shares validly tendered and not properly withdrawn in the tender offer.
Following acceptance of the tendered shares, Medtronic completed its acquisition of HeartWare through the merger of Medtronic Acquisition Corp. with and into HeartWare without a vote of HeartWare’s stockholders pursuant to Section 251(h) of the Delaware General Corporation Law. As a result of the merger, HeartWare became a wholly-owned subsidiary of Medtronic. In connection with the merger, all HeartWare shares not validly tendered into the tender offer (other than shares (i) owned by HeartWare as treasury stock or owned by Medtronic, Inc. or Medtronic Acquisition Corp., which shares were cancelled and retired and cease to exist or (ii) held by any person who was entitled to and has properly demanded statutory appraisal of his or her shares) have been cancelled and converted into the right to receive the same $58.00 per share in cash, without interest, subject to any required withholding of taxes, as will be paid for all shares that were validly tendered and not properly withdrawn in the tender offer. HeartWare common stock will cease to be traded on The NASDAQ Stock Market LLC.
About Medtronic Medtronic plc (www.medtronic.com), headquartered in Dublin, Ireland, is among the world’s largest medical technology, services and solutions companies – alleviating pain, restoring health and extending life for millions of people around the world. Medtronic employs more than 85,000 people worldwide, serving physicians, hospitals and patients in approximately 160 countries. The company is focused on collaborating with stakeholders around the world to take healthcare Further, Together.
Two-year outcomes from the National Institutes of Health (NIH)–sponsored Cardiac Surgery Clinical Research Network (CTSN) trial suggest that patients with severe ischemic mitral regurgitation (MR) fare just as well when the valve is repaired or replaced, at least when it comes to measures of left ventricular reverse remodeling and survival, but that replacing the mitral valve provides a more durable correction of MR[1].
Presenting the results of the CTSN trial here at the American Heart Association (AHA) 2015 Scientific Sessions, the researchers reported no significant difference in the mean left ventricular end-systolic volume index (LVESVI) among 251 patients randomized to mitral-valve repair or chordal-sparing mitral-valve replacement.
In addition, there was no mortality advantage with either approach. The 2-year mortality rate was 19.0% in the repair arm and 23.2% in the replacement group, a difference that was not statistically significant (hazard ratio 0.79; 95% CI 0.46–1.35).
Despite the equivocal results, investigators, including lead researcher Dr Daniel Goldstein (Montefiore Medical Center/Albert Einstein College of Medicine, New York), did observe significantly higher recurrence rates among patients who underwent surgical repair. At 2 years, 59% of patients in the repair arm and 3.8% in the replacement arm were diagnosed with moderate or severe MR (P<0.001).
“Recurrence was rather striking,” said Goldstein during a press conference announcing the results. “Interestingly, most of the recurrences were moderate, were not severe.”
This difference in MR translated into a significantly increased risk of heart failure at 2 years among patients undergoing mitral-valve repair (24.0% vs 15.2% in the repair and replacement arms, respectively; P=0.05) as well as an increased readmission rate to hospital for cardiovascular causes (48.3% vs 32.2%, respectively;P=0.01).
Dr Daniel Goldstein
“There was no difference in the total readmissions to the hospital between groups,” said Goldstein. “However, if you look at just cardiovascular readmissions, there was a striking difference, with repair patients requiring many more heart-failure readmissions than replacement patients. What were those heart-failure readmissions for? They were for true heart failure or for the placement of an ICD or biventricular pacers, which in essence are also heart-failure readmissions because the people who are getting those technologies are people with advanced heart failure.”
The bottom line, say investigators, is that the 2-year data reveal a divergence in clinical outcomes not evident at 1 year. The deficiency in the durability of correction of MR with surgical repair is “disconcerting,” they add, noting that MR recurrence predisposes patients to heart failure, atrial fibrillation, increased hospitalizations, and other adverse outcomes.
The 2-year results are published November 9, 2015 in the New England Journal of Medicine to coincide with the late-breaking clinical-trials presentation. One-year outcomes presented at the AHA 2013 meeting and reported by heartwirefrom Medscape at that time.
Who Should Get Repair? Who Replacement?
Dr Alain Carpentier (Descartes University, Paris, France), one of the world leaders in mitral-valve repair, said the findings are particularly important for younger, less experienced surgeons. “If these results are confirmed, it means that the young surgeon with little experience in valve repair shouldn’t feel guilty for replacing a valve because he or she will be certain that the result will be as good.”
Valve repair, added Carpentier, is a “question of experience” and should be done only by surgeons with a large amount of clinical practice in the surgical technique. The present study is unique as the surgeons performing the procedure in BEAT-HF were experienced surgeons, a component of the trial that partially explains why repair and replace both fared as well in terms of the primary end point.
Speaking with the media, Goldstein said physicians who support valve repair believe it is associated with lower morbidity and mortality, noting that it results in the preservation of the entire mitral subvalvular apparatus. MR recurrence is a known problem, however, and this can lead to functional mitral stenosis if the ring is very small. Replacement, on the other hand, is associated with higher perioperative morbidity and mortality, but it does provide a more durable correction of MR.
Goldstein said that even though there was no difference in LVESVI at 2 years or in mortality either, recurrence is a factor that will weigh in a decision over whether or not to repair or replace the mitral valve. Right now, he is comfortable performing a mitral-valve replacement as first-line treatment in a majority of patients. “I think we still need to follow these patients a little longer, because you have to remember you have a prosthesis in there,” he said. “The prosthesis can give you problems. There’s thromboembolic complications, it can get infected, it can deteriorate and need rereplacement, so the balance of those issues awaits more time.”
That said, in the absence of reliable predictors of a successful mitral-valve repair, surgical replacement of the mitral valve is a viable option. “Based on experience, I think a lot of people want to start thinking a little more liberally about replacing the valve in general just because of these data,” he said. Optimal valve-replacement candidates would include individuals with a basal aneurysm or basal dyskinesia, he noted.
Goldstein reports grant support from the National Institutes of Health and consulting fees from Medtronic. Disclosures for the coauthors are listed on the journal website.
UPDATED Sept. 10, 2015, with details on MVAD trial pause, expanded field action and Valtech acquisition.
HeartWare International (NSDQ:HTWR) today said it’s pausing enrollment in a clinical trial of its next-generation MVAD heart pump while it looks to fix an issue with the manufacturing process for the left ventricular assist device’s controller.
“There was a feeding frenzy starting to develop around Valtech. We agreed with them that we would put in a 2nd investment earlier this year that would buy us an exclusivity period that expired mid-September. It was quite clear from the communications we were getting from the company that they were having to fend off interest from others. It was also quite clear from the company that they are an R&D powerhouse that doesn’t really want to build a commercial organization,” he said. “Frankly if we couldn’t do Valtech, we weren’t going to do mitral because we believe we need the ability to repair surgically and repair interventionally and we believe we need a portfolio.”
Implications of this M&A on the Global EcoSystem for Carviovascular Repair Tools Segment
September 6, 2015
It is my strong belief that HeartWare inked $929m deal for Valtech Cardio’s mitral and tricuspid valves Is creating a new constellation of concentration among players, thus M&A could be the optimal solution as a fallout from the new reality of $1Billion investment in Israeli Valtech, for many Early stage Start Ups in the Mitral Valve Repair and Replacement Segment.
What implications this deal has on the Mitral Valve Repair Technology Start Ups vs Mitral Valve Replacement OEM of Artificial Valves?
Percutaneous Annuloplasty May Offer Safe, Effective Alternative to Surgery for HF Patients With MR
What are the Market implications of this announcement on
Medtronic
Edwards LifeSciences
St. Jude (new announcement)
Abbot
In addition,
Lev-Ari, A. 6/22/2012Competition in the Ecosystem of Medical Devices in Cardiac and Vascular Repair: Heart Valves, Stents, Catheterization Tools and Kits for Open Heart and Minimally Invasive Surgery (MIS)
Lev-Ari, A. 6/19/2012Executive Compensation and Comparator Group Definition in the Cardiac and Vascular Medical Devices Sector: A Bright Future for Edwards Lifesciences Corporation in the Transcatheter Heart Valve Replacement Market
Lev-Ari, A. 6/22/2012Global Supplier Strategy for Market Penetration & Partnership Options (Niche Suppliers vs. National Leaders)in the Massachusetts Cardiology & Vascular Surgery Tools and Devices Market for Cardiac Operating Rooms and Angioplasty Suites
Medtronic (NYSE:MDT) said today that it agreed to pony up as much as $458 million for Twelve Inc. and its transcatheter mitral valve implant, as the race to get a TMVI device to market heats up.
Twelve, a spinout from the Foundry incubator that’s based in Redwood City, Calif., is backed by Domain Associates, Versant Ventures, Morgenthaler Ventures, Longitude Capital, Emergent Medical Partners, Vertex Venture Management, and Capital Group, Fridley, Minn.-based Medtronic said.
The deal calls for a $408 million payment once the deal closes, expected in October, and another $50 million pegged to CE Mark approval in the European Union for the Twelve TMVI device.
“Upon close, this acquisition will strategically augment our existing capabilities in the transcatheter mitral space, which represents an important growth opportunity for Medtronic,” coronary & structural heart president Sean Salmon said in prepared remarks. “We have followed the transcatheter mitral valve space closely and firmly believe that Twelve has the most novel technology along with a strong, proven team. The combined strengths of our organizations will significantly accelerate our ability to deliver an exciting and differentiated therapy to patients, physicians and healthcare systems around the world.”
Edwards Lifesciences (NYSE:EW) last week said it agreed to pay $400 million for CardiAQ Valve Technologies and its transcatheter mitral valve implant, saying it also reached a deal to revise the protocol for restarting a trial of its own Fortis mitral valve.
The deal for CardiAQ Valve, which like Edwards is based in Irvine, Calif., calls for an up-front payment of $350 million in cash and another $50 million pegged to “achievement of a European regulatory milestone,” Edwards said. The deal is expected to be “slightly dilutive” to 2015 earnings, the company said.
“Edwards’ primary strategy is to create valuable therapies that transform patient care. We believe the acquisition and integration of CardiAQ will advance our development of a transformational therapy for patients with mitral valve disease who aren’t well-served today,” chairman & CEO Michael Mussallem said in prepared remarks. “While still early in the development of this therapy, the progress of the team of employees and clinicians working on our Fortis mitral replacement system has reinforced our confidence in a catheter-based approach. We believe the experiences and technologies of Fortis and CardiAQ are complementary and that this combination will enable important advancements for patients.”
“CardiAQ is proud of our pioneering efforts in the early development of this transcatheter mitral valve therapy conceived by cardiac surgeon Dr. Arshad Quadri. We believe our technology, which incorporates multiple delivery approaches with a single valve, shows great promise for patients,” added CardiAQ CEO Rob Michiels.
In April, CardiAQ won an investigational device exemption from the FDA for a 20-patient feasibility trial of its as-yet-unnamed TMVI candidate, with a protocol calling for 10 subjects to be treated transfemorally and another 10 treated via the transapical approach.
“We look forward to joining Edwards, whose experience and leadership as a developer of breakthrough therapies for heart valve disease will advance our work,” co-founder, president & COO Brent Ratz said in a statement.
Edwards also said it reached a deal with the investigators in its Fortis trial for changes to study’s protocol, after blood clots in some of the 20 patients implanted with the device prompted a temporary halt for the trial.
Abbott’s percutaneous MitraClip mitral valve repair device SUPERIOR to Pacemaker or Implantable Cardioverter Defibrillator (ICD) for reduction of Ventricular Tachyarrhythmia (VT) episodes
Harpoon Medical is a development stage medical device company commercializing a minimally invasive, image guided surgical tool for beating heart mitral valve repair. The technology was developed in the Division of Cardiac Surgery at The University of Maryland School of Medicine. With the Harpoon device, surgeons can access and repair the mitral valve in a beating heart via a small incision between the ribs without the need for cardiac arrest or cardiopulmonary bypass. The tool enters the left ventricle transapically and inserts “bulky knot” neochords in the leaflet to eliminate mitral valve regurgitation. When introduced to the market, the Harpoon device should transform the traditional open heart mitral valve surgical procedure from a complex 3-6 hour operation to a 60-minute procedure and reduce the recovery period from weeks to days.
Mitral-Valve Repair versus Replacement for Severe Ischemic Mitral Regurgitation
Michael A. Acker, M.D., Michael K. Parides, Ph.D., Louis P. Perrault, M.D., Alan J. Moskowitz, M.D., Annetine C. Gelijns, Ph.D., Pierre Voisine, M.D., Peter K. Smith, M.D., Judy W. Hung, M.D., Eugene H. Blackstone, M.D., John D. Puskas, M.D., Michael Argenziano, M.D., James S. Gammie, M.D., Michael Mack, M.D., Deborah D. Ascheim, M.D., Emilia Bagiella, Ph.D., Ellen G. Moquete, R.N., T. Bruce Ferguson, M.D., Keith A. Horvath, M.D., Nancy L. Geller, Ph.D., Marissa A. Miller, D.V.M., Y. Joseph Woo, M.D., David A. D’Alessandro, M.D., Gorav Ailawadi, M.D., Francois Dagenais, M.D., Timothy J. Gardner, M.D., Patrick T. O’Gara, M.D., Robert E. Michler, M.D., and Irving L. Kron, M.D. for the CTSN
Ischemic mitral regurgitation is associated with a substantial risk of death. Practice guidelines recommend surgery for patients with a severe form of this condition but acknowledge that the supporting evidence for repair or replacement is limited.
METHODS
We randomly assigned 251 patients with severe ischemic mitral regurgitation to undergo either mitral-valve repair or chordal-sparing replacement in order to evaluate efficacy and safety. The primary end point was the left ventricular end-systolic volume index (LVESVI) at 12 months, as assessed with the use of a Wilcoxon rank-sum test in which deaths were categorized below the lowest LVESVI rank.
RESULTS
At 12 months, the mean LVESVI among surviving patients was 54.6±25.0 ml per square meter of body-surface area in the repair group and 60.7±31.5 ml per square meter in the replacement group (mean change from baseline, −6.6 and −6.8 ml per square meter, respectively). The rate of death was 14.3% in the repair group and 17.6% in the replacement group (hazard ratio with repair, 0.79; 95% confidence interval, 0.42 to 1.47; P=0.45 by the log-rank test). There was no significant between-group difference in LVESVI after adjustment for death (z score, 1.33; P=0.18). The rate of moderate or severe recurrence of mitral regurgitation at 12 months was higher in the repair group than in the replacement group (32.6% vs. 2.3%, P<0.001). There were no significant between-group differences in the rate of a composite of major adverse cardiac or cerebrovascular events, in functional status, or in quality of life at 12 months.
CONCLUSIONS
We observed no significant difference in left ventricular reverse remodeling or survival at 12 months between patients who underwent mitral-valve repair and those who underwent mitral-valve replacement. Replacement provided a more durable correction of mitral regurgitation, but there was no significant between-group difference in clinical outcomes.
(Funded by the National Institutes of Health and the Canadian Institutes of Health; ClinicalTrials.gov number, NCT00807040.)
Verna Hoy knew something wasn’t right; she was coughing a lot and running out of breath. Both her mother and a sister had heart murmurs — which doctors heard in Hoy’s chest, too — so she wasn’t surprised to be referred to a cardiologist.What cardiologists found would not be so simple to fix, however. At least, it didn’t use to be. Hoy had two problems: a leaky mitral valve in her heart, which caused blood to back up into her left atria, and something called hypertrophic cardiomyopathy (HCM) that obstructed blood flow in her heart. And the only way to fix it, before, was risky and invasive open heart surgery. But doctors didn’t want to do that to the 87-year-old from Richfield.Instead, her cardiologist turned to a just-approved device called a MitraClip that could be deployed via a catheter snaked up to her heart through a vein in her leg.On Dec. 11, Hoy became the first patient in Minnesota to receive the MitraClip to repair a leaky mitral valve. Turns out, Hoy also is the first person in the world to also have her HCM treated with the same device.“They decided they would try this procedure to see if it would work,” Hoy said recently. Its seems to be working just fine. A week after her procedure, Hoy was washing clothes, running errands to the grocery store and drugstore and heading out to lunch.”We’re all very excited about it,” said Dr. Paul ?Sorajja, an interventional cardiologist at the Minneapolis Heart Institute Foundation and Abbott Northwestern Hospital. “This is a new advance in the management of patients with HCM.”The combination of HCM and a faulty mitral valve affects 400,000 Americans. The MitraClip, developed by Abbott Laboratories, won approval from the Food and Drug Administration in October. It has been available in Europe for several years.
The MitraClip is the only commercially available mitral valve repair device that can be placed into the heart through a blood vessel, a much less-invasive process that speeds patient healing.
Sorajja and Dr. Wes Pedersen, director of the Transcatheter Valve Therapy Program at the Minneapolis Heart Institute, were investigators into the safety and effectiveness of the procedure during clinical trials.
“The device has proved its effectiveness in research studies and we are excited to see this device commercially available and improving and extending the lives of thousands of people,” Sorajja said. “When we looked at how this device can be used to treat mitral regurgitation, we felt that it could also be used to simultaneously treat obstruction due to HCM.”
HCM is a condition in which the walls of the heart thicken, interfering with the heart’s activities. In Hoy’s case, a thick wall in her left ventricle slowed the flow of blood out of the ventricle. At the same time, the thickening caused the mitral valve in her heart to leak blood into her left atrium — called mitral regurgitation. That combination was hurting Hoy.
For patients with HCM, doctors usually open the chest to remove part of the thickened heart wall. In some cases, they inject alcohol into the tissue to kill it, causing a small heart attack. But the MitraClip, which essentially clips the middle of the leaky mitral valve, also keeps that valve from further obstructing blood flow, Sorajja said. One device, two problems solved.
According to the FDA, repairing the valve during open heart surgery still is the preferred method. But MitraClip is now acceptable for patients who are not considered healthy enough for the surgery.
Sorajja, who came to Abbott Northwestern from the Mayo Clinic, said, “We had our suspicions that this would work. It was a great day. It was a really great day for us. We are so happy.”
Hoy, who was discharged from the hospital just two days after the procedure, said she still gets a little breathless.
“I seem to be OK,” she said. “I was told not to lift anything over 10 pounds and I watch it.”
She said trying a new device didn’t worry her. Besides, she likes the idea of maybe helping others with what doctors learn from her.
“There are a lot of people on this Earth,” she said. “If it is my time, so be it. But I thought if it would help other people, I would take a shot.” ___
A. Who is a Patient Candidate for a Non-Ablative Fully Non-Invasive Procedure?
A.1 Patient Segments by Medical Diagnosis
If a patient is disqualified for CABG then the patient is likely to be disqualified for Open Heart Surgery for Mitral Valve Repair and Replacement.
For all cases that a percutaneous Transcatheter for Mitral Valve Repair is deemed to be non indicated – the patient’s SOLE choice is the proposed Non-Ablative Fully Non-Invasive Procedure – a novel technology under development by Dr. Pearlman.
Special Patient Subsets
A. Elderly Patients
Elderly patients being considered for CABG have a higher average risk for mortality and morbidity in a direct relation to age, LV function, extent of coronary disease, and comorbid conditions and whether the procedure is urgent, emergent, or a reoperation. Nonetheless, functional recovery and sustained improvement in the quality of life can be achieved in the majority of such patients. The patient and physician together must explore the potential benefits of improved quality of life with the attendant risks of surgery versus alternative therapies that take into account baseline functional capacities and patient preferences. Age alone should not be a contraindication to CABG if it is thought that long-term benefits outweigh the procedural risk.
B. Women
A number of earlier reports had suggested that female sex was an independent risk factor for mortality and morbidity after CABG. More recent studies have suggested that women on average have a disadvantageous, preoperative clinical profile that accounts for much of this perceived difference. Thus, the issue is not necessarily sex itself but the comorbid conditions that are particularly associated with the later age at which women present for coronary surgery. Thus, CABG should not be delayed in or denied to women who have appropriate indications.
ACC/AHA Practice Guidelines, ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery: Executive Summary and Recommendations. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1991 Guidelines for Coronary Artery Bypass Graft Surgery)
Current existing guidelines do not recommend surgery for asymptomatic or mildy symptomatic patients1, there is a large cohort of patients with significant mitral regurgitation that do not undergo surgery, thus allowing for observational studies of outcomes in non-surgically treated patients.
Before expanded application of mitral valve repair in the 1990s, cohorts of symptomatic patients with mitral valve prolapse were followed on medical therapy allowing determination of natural history of mitral regurgitation.
Mitral valve prolapse with severe regurgitation reduces long-term survival irrespective of medical therapy. It appears that the prolapse itself is not the cause of mortality or morbidity (cardiac event rates are extremely low for the entire population with prolapse), but it is
severe regurgitation and consequent left ventricular dilatation that results in morbidity2, 3. Heart failure, arrhythmia, endocarditis and stroke are the leading causes of death.
Enriquez-Sarano and colleagues have performed analyses to define which group of patients with mitral regurgitation are at greatest risk of cardiac events4, 5, 6.
Notably, when considering asymptomatic patients, the greater the severity of mitral regurgitation (preferably determined by quantitative echocardiography), the higher the frequency of cardiac events irrespective of a normal ventricular function (Figure 1).
Other risk factors for cardiovascular morbidity include
Presence of these factors implies a reduced life expectancy if mitral regurgitation is uncorrected. Current evidence from surgical cohorts, suggests that mitral valve repair (assuming an operative mortality below 1%) yields a better outcome (survival and freedom from cardiac events) compared to the outcomes observed in non-surgically treated patients with severe regurgitation. For example
Mitral valve repair in patients with good ventricular function has a long term survival similar to expected survival in age matched cohorts5, 8, 9, whereas long term follow-up of patients with mitral valve prolapse treated medically shows a reduced survival compared to expected survival10 (Figure 2).
In the U.S. over 5 million patients are estimated to suffer from moderate to severe mitral regurgitation with an additional 300,000+ new patients diagnosed annually. In Western Europe the number is comparable and other medically advanced countries around the world add to this addressable patient population. The rest of the world market has been assumed to be equal to twice the size of the US market.
Of these over 5 million patients in the US, about 130,000 have annuloplasty surgeries every year (about 65% repair and 35% replacement). Another 700,000 are deemed high risk. These high risk patients represent a non-served market because there is no non-implantable device/simpler surgical procedure available.
Due to the surgical probe and lateral device’s inherent simplicity of application compared to current implantable techniques, ValveCure forecasts that in addition to capturing some of the current annuloplasty procedures, a large number of currently unserved mitral regurgitation patients will avail themselves of this new technology.
Surgical treatment of mitral regurgitation (MR) has evolved from mitral valve replacement (MVR) to repair (MVRe), because MVRe produces superior long-term outcomes. In addition, MVRe can be achieved through minimally invasive approaches. This desire for less invasive approaches coupled with the fact that a significant proportion of patients—especially elderly persons or those with significant comorbidities or severe left ventricular (LV) dysfunction, are not referred for surgery, has driven the field of percutaneous MVRe. Various technologies have emerged and are at different stages of investigation. A classification of percutaneous MVRe technologies on the basis of functional anatomy is proposed that groups the devices into those targeting the leaflets (percutaneous leaflet plication, percutaneous leaflet coaptation, percutaneous leaflet ablation), the annulus (indirect: coronary sinus approach or an asymmetrical approach; direct: true percutaneous or a hybrid approach), the chordae (percutaneous chordal implantation), or the LV (percutaneous LV remodeling). The percutaneous edge-to-edge repair technology has been shown to be noninferior to open repair in a randomized clinical trial (EVEREST II [Endovascular Valve Edge-to-Edge REpair Study]). Several other technologies employing the concepts of direct and indirect annuloplasty and LV remodeling have achieved first-in-man results. Most likely a combination of these technologies will be required for satisfactory MVRe. However, MVRe is not possible for many patients, and MVR will be required. Surgical MVR is the standard of care in such patients, although percutaneous options are under development.
“LPBI Proposals for Precision Mitral Annuloplasty: Extensions to RF Solutions and MRI Methods and Devices”
Inventor and Author:Justin D Pearlman, MD, PhD, FACC
The primary goal for therapy of mitral regurgitation is reduction in the leakage without causing stenosis (excessive flow resistance), prior to the development of fibrosis of heart muscle secondary to abnormal workload. The specific treatment can be adapted to the specific mechanism of the valve leakage. Mechanisms of mitral regurgitation include prolapse (leaflet inversion) due to a large excessively flexible leaflet and/or excessive length of chordae, malcoaptation/incomplete valve closure assocated with relatively large or dilated annular support, or rarely, perforation of a leaflet. Shrinkage of excessive tissue can be achieved surgically or non-surgically. Under non-disclosure we can elaborate on proprietary methods that can achieve these goals surgically or non-surgically, either with direct contact (invasive) but without requiring cardiac bypass, robotic catheter (minimally invasive) or with no skin breach at all (completely non-invasive).
C.1 Three extensions of ValveCure Non-Hardware Surgical Mitral Annuloplasty
C.2 Three non-Surgical Alternatives to RF Mitral Annuloplasty: Response Modulated Excitation – MRi Methods and Devices
C.3 Features of Novel Technology: MRI Methods and Devices
Three extensions of Current Non-Hardware Surgical Mitral Annuloplasty
Three Less Invasive methods
For the full presentation go to the link, below and request access for the PASSWORD PROTECTED Article by e-mailing to the inventor
Dr. David H. Adams is the Marie-Josée and Henry R. Kravis Professor and Chairman of the Department of Cardiothoracic Surgery at The Mount Sinai Medical Center. Dr. Adams is a leader in the field of mitral valve reconstruction and heart valve surgery. As Program Director of Mount Sinai’s Mitral Valve Repair Reference Center, he has set national benchmarks for the specialty with a repair success rate of more than 99 percent in patients with degenerative mitral valve disease, while running one of the largest and most respected valve programs in the United States.
Dr. Adams’ impact extends far beyond his own operating room. As the holder of multiple patents, he carries out a prodigious research agenda to develop new techniques and tools to push frontiers in complex valve surgeries and make procedures safer for patients. He is the co-inventor of two mitral valve annuloplasty repair rings (the Carpentier-Edwards Physio II Annuloplasty Ring and the Carpentier-McCarthy-Adams IMR ETlogix Ring), and inventor of a new tricuspid annuloplasty ring (Medtronic Tri-Ad Tricuspid Annuloplasty Ring) and has royalty agreements with Edwards Lifesciences andMedtronic. Dr. Adams has performed the first successful implantations of the IMR ETlogix, Physio II, and Tri-Ad Rings in the United States. All of these rings are now used extensively throughout the world.
Dr. Adams is a much sought after speaker both nationally and internationally and has given over 300 invited lectures and operated on patients in multiple teaching courses throughout the world. His desire to share knowledge and collaborate with other cardiac surgeons led him to develop one of the world’s largest video libraries of techniques in valve reconstruction. He is the author of over 200 publications, and is recognized as a leading surgeon scientist and medical expert, serving on the Editorial Boards of several medical journals, including Cardiology and The Annals of Thoracic Surgery. He is currently the Co-Editor of Seminars in Thoracic and Cardiovascular Surgery. Dr. Adams has served in an advisory capacity to essentially all industry leaders in cardiovascular surgery. He also serves as the National Co-Principal Investigator of the United States FDA pivotal trial of the Medtronic CoreValve Transcatheter Aortic Valve replacement device.
Dr. Adams’ clinical interests include all aspects of heart valve surgery, with a special emphasis on mitral valve reconstruction and multiple valve surgery. His major research interests include outcomes related to mitral valve repair, novel mitral valve repair strategies, and percutaneous valve replacement. Past research honors include the Alton Ochsner Research Scholarship from the American Association for Thoracic Surgery and the Paul Dudley White Research Fellowship from the American Heart Association. He has also received honorary Professorships from Capital University in Beijing and Keio University in Tokyo. In 2009, he received the New York American Heart Association Award for Achievement in Cardiovascular Science and Medicine.
Dr. Adams received his undergraduate and medical education at Duke University and completed his internship and residency in general and cardiothoracic surgery at Brigham and Women’s Hospital and at Harvard Medical School. Dr. Adams followed that with a fellowship in London under Professor Sir Magdi Yacoub. In addition, he completed a two-year research fellowship under Professor Morris Karnovsky in the Department of Pathology at Harvard Medical School. He later served at Brigham and Women’s Hospital as the Associate Chief of Cardiac Surgery. He has been Chairman of the Department of Cardiothoracic Surgery at The Mount Sinai Medical Center since 2002.
David H. Adams, MD
Marie-Josée and Henry R. Kravis
Professor and Chairman
Department of Cardiothoracic Surgery
The Mount Sinai Medical Center
New York, NY 10029
212-659-6820
Essentially, all degenerative mitral valves are repairable. By matching echocardiographic findings to the appropriate surgical skill level required to consistently deliver a repair, valve replacement for degenerative mitral valve disease should be infrequent.
Most patients with mitral regurgitation remain asymptomatic for long periods of time. The most common presenting signs and symptoms include fatigue, decreased exercise capacity, shortness of breath, and palpitations or supra-ventricular arrhythmias such as atrial fibrillation. Auscultatory examination usually reveals a high-pitched systolic murmur radiating from the apex to the axilla. A holosytolic murmur suggests prolapse simultaneous with ejection typical of chordal rupture, whereas a murmur beginning in mid- or late systole favors billowing or chordal elongation. Radiographic findings may include left atrial and ventricular dilatation and prominent pulmonary vasculature in patients with long standing severe mitral regurgitation. The electrocardiogram may be normal, or show evidence of left atrial enlargement or atrial fibrillation.
Table 1: Selected ranges for grading severity of mitral regurgitation. Rvol, regurgitation volume, ERO, effective regurgitant orifice1, 2.
Two dimensional echocardiography with doppler is essential to determine the mechanism (dysfunction) and severity of mitral regurgitation. Semi-quantitative assessment of regurgitant flow using maximal jet length, area, and ratio of jet to left atrial area is recommended to assess the severity of mitral regurgitation1. Regurgitant jet geometry and area are assessed in multiple views and mitral regurgitation severity is graded typically as a rank order variable (e.g. 1+ trace, 2+ mild, 3+ moderate and 4+ severe mitral regurgitation). The direction of the jet provides evidence of segmental involvement as it is typically opposite to the prolapsing segment. Quantitative doppler grading of mitral regurgitation is gaining in popularity and is based on the calculation of regurgitant volume (the difference between the mitral and aortic stroke volumes) and effective regurgitant orifice (ratio of regurgitant volume to regurgitant time velocity integral). Table 1 shows the correlation between the semi-quantitative and quantitative grading of mitral regurgitation in degenerative mitral disease. Transesophageal echocardiography (TEE) is a useful adjunct to confirm the diagnosis and understand the mechanism of degenerative valve disease in the case of a non-definitive transthoracic examination. Experience is also gaining with three dimensional echocardiography in the assessment of annular geometry and leaflet dysfunction in the setting of mitral regurgitation, and can be predicted to have a more significant role in planning reparative procedures in the future.
(1) Zoghbi WA, Enriquez-Sarano M, Foster E et al. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003 July;16(7):777-802.
(2) Dujardin KS, Enriquez-Sarano M, Bailey KR, et al: Grading of mitral regurgitation by quantitative Doppler echocardiography: calibration by left ventricular angiography in routine clinical practice. Circulation 96(10):3409-15 1997.
In the hands of reference mitral valve-repair surgeons, 95–100% of degenerative valves are repairable, regardless of etiology; however, in the general cardiac surgical community, the repair rates are around 50%. In contrast to fibroelastic deficiency, Barlow’s valves have more complex pathology and require advanced techniques to effect a repair.
Mitral valve regurgitation is present when the valve does not close completely, causing blood to leak back into the left atrium. Mitral valve stenosis is present when the valve does not open completely, causing a relative obstruction to blood flow. Both of these conditions increase the workload on the heart and are very serious conditions. If left untreated, they can lead to debilitating symptoms including cardiac arrhythmia, congestive heart failure, and irreversible heart damage.
Figure 1: Carpentier’s functional classification. Type I, normal leaflet motion; Type II, increased leaflet motion (leaflet prolapse); Type IIIa restricted leaflet motion during diastole and systole; Type IIIb restricted leaflet motion predominantly during systole.*
Carpentier refers to the confusion surrounding classification and description of mitral valve disease as “the Babel Syndrome,” in reference to the Biblical story of what happens when workers do not speak the same language1. Degenerative mitral valve disease is the best example of this phenomenon, where terms such as prolapse, flail, partial flail, billowing, Barlow’s disease, floppy valve, and myxomatous valve disease are often used inter-changeably by different specialists, blurring the distinction between valve dysfunction and disease. Carpentier’s pathophysiologic triad1describes the inter-relationship between etiology (the cause of the disease), lesions (the result of the disease) and leaflet motion dysfunction (which results from the lesions). Carpentier’s classification of dysfunction is based on the opening and closing motions of the mitral leaflets in relation to the annular plane (Figure 1). It is in this context that degenerative mitral valve disease is best understood.
The most common leaflet dysfunction in degenerative valve disease is Type II, excess motion of the margin of the leaflet in relation to the annular plane. The lesions in degenerative valve disease that result in the Type II dysfunction are usually chordae elongation or rupture. Annular dilatation is almost always an associated finding. The most common diseases that cause degenerative mitral valve disease are Barlow’s disease and fibroelastic deficiency (Figure 2). Barlow’s disease, first described in the 1960s2, is characterized by several distinguishing features. Excess leaflet tissue with large billowing and thickened leaflets is a hallmark of Barlow’s disease, and the annular size is quite large. The chordae tendinae tend to be thickened and have a mesh type appearance in their insertion in the body of the leaflets. Chordal elongation is the most common cause of prolapse, and multiple leaflet segments are usually involved. It generally occurs in younger patients (aged
In contrast, fibroelastic deficiency is a degenerative disease of older individuals (usually >60 years of age), with a shorter history of valve regurgitation3. Rupture, often of a single chord, is the most common cause of leaflet dysfunction in fibroelastic deficiency, and in most cases the only abnormal leaflet tissue is found in the prolapsing segment. The other leaflet segments are often thin and translucent, and of normal height. The posterior annulus may be dilated, but the size of the anterior leaflet and valve are most often normal.
Type I dysfunction with normal leaflet motion and pure annular dilatation is a less common form of degenerative valve disease. It may be associated with conditions that result in significant atrial dilatation such as long-standing atrial fibrillation, or may occur in patients with connective tissue disorders.
(*) Modified from Carpentier A, Adams DH, Filsoufi F. Carpentier’s Reconstructive Valve Surgery. From Valve Analysis to Valve Reconstruction. 2010 Saunders Elsevier.
(1) Carpentier A. Cardiac valve surgery–the “French correction”. J Thorac Cardiovasc Surg1983 September;86(3):323-37.
(2) Barlow JB, Pocock WA. The significance of late systolic murmurs and mid-late systolic clicks. Md State Med J1963 February;12:76-7.
(3) Carpentier A, Chauvaud S, Fabiani JN et al. Reconstructive surgery of mitral valve incompetence: ten-year appraisal. J Thorac Cardiovasc Surg1980 March;79(3):338-48.
Portions excerpted, with permission, Adams DH, Anyanwu AC. The cardiologist’s role in increasing the rate of mitral valve repair in degenerative disease. Current Opinion in Cardiology 2008, 23:105–110.
A.2 Barlow Mitral Valve Disease
The syndrome of mid-systolic click accompanying a systolic murmur was first described in the late 1800s, but it was in the early 1960s that its association with mitral regurgitation was demonstrated by Barlow and colleagues using cine-ventriculography1. Criley et al.2 correctly identified the mechanism of the regurgitation as posterior leaflet prolapse due to excess leaflet motion, coining the phrase ‘mitral valve prolapse’. Carpentier and co-workers later characterized the surgical lesions resulting from the myxoid degeneration present in Barlow’s disease, which included leaflet thickening, large redundant leaflets, chordal elongation or rupture, and annular dilatation. As the myxoid degenerative process often affects the entire valve, patients with Barlow’s disease generally have complex valve pathology and dysfunction, which is most often multisegmental (i.e. involves more than one segment of the posterior or anterior leaflet).
Clinical Presentation
Figure 1: ((a) Transesophageal echocardiography 4 chamber view showing bileaflet billowing with prolapse, large valve size, and thickened leaflet, all hallmarks of Barlow’s disease. (b) Surgical view of the same valve shows thickened tall prolapsing leaflets with excess tissue. (c) Valve has been successfully repaired after ‘complex’ bi-leaflet plasty. Repairs of this nature can only be reproducibly undertaken by reference mitral surgeons – in nonreference settings this valve would generally be replaced.
Patients with Barlow mitral-valve disease are generally adults around the age of 50 years who have known for a long period of time, often decades, that they ‘have a murmur’. Often asymptomatic, patients may have been followed by an internist for years, and referral to a cardiologist and subsequently to a cardiac surgeon is usually triggered by the development of symptoms or signs such as atrial fibrillation, shortness of breath and fatigue, or echocardiographic documentation of ventricular or atrial enlargement, or a decline in ventricular function, often accompanied by varying degrees of pulmonary hypertension. Physical examination most often reveals the presence of a mid-systolic click and a mid to late systolic murmur, which reflects the timing of prolapse in the setting of excess tissue and chordal elongation without chordal rupture (i.e. flail leaflet)2.
Echocardiographic Findings
Echocardiography is a sensitive tool in the differentiation of degenerative mitral valve disease. A striking feature of the patient with Barlow’s disease is the size of the valve apparatus – the leaflets are usually thick, bulky, elongated, and distended; the chords thickened and elongated, often mesh-like in nature; and the annulus dilated and enlarged, often times greater than 36mm in the intercommissural distance (Figure 1). The prolapse is often multisegmental, and involves both leaflets in up to 40% of patients3. The insertion of the posterior leaflet is often displaced toward the left atrium away from its normal insertion in the atrio-ventricular groove, creating a cul-de-sac at the base of the leaflet. The bodies of distended leaflet segments often billow above the plane of the annulus, and the margin of the leaflet segments prolapse in mid-systole in the setting of chordal elongation, or in early systole if chordal rupture has occurred. Calcification of the annulus and papillary muscles may be present. Real time three-dimensional echocardiography is allowing additional clarity of the segmental nature of the billowing, as well as prolapse, in Barlow’s disease4,5,6 and may play a critical role in the preoperative work up of these patients in the future.
Surgical Considerations
The complexity of surgical lesions in Barlow mitral-valve disease is consistent with the echocardiographic findings (Figure 1). Lesions include excessively thick and billowing leaflet segments, chordal elongation and chordal rupture, calcification of the papillary muscles and/or annulus with chordae restriction, and severe annular dilatation with giant valve size. It is important that the cardiologist as well as the surgeon has an appreciation for these lesions, as the complexity of techniques required to achieve a successful repair then becomes obvious in this subset of degenerative mitral-disease patients. Dealing with excess tissue height is an important consideration to reduce the likelihood of postoperative systolic anterior motion. Repair of Barlow valves is thus more complicated and, in our experience, often requires multiple different techniques and 2–3 hours to remove all of the diseased tissue, and reconstruct the leaflets to a normal configuration3.
Table 1: Targeting referral pattern to optimize repair rates.
To achieve a Barlow repair, the surgeon therefore needs to be well versed with various advanced mitral repair techniques, such as extensive leaflet resection, sliding leaflet plasty, chordal transfer, neochordoplasty, commissuroplasty, annular decalcification and use of large annuloplasty rings. Patients with advanced forms of Barlow’s disease will therefore likely have a high probability of successful valve repair only if done in reference centers by mitral subspecialists (Table 1).
Excerpted, with permission, Adams DH, Anyanwu AC. The cardiologist’s role in increasing the rate of mitral valve repair in degenerative disease. Current Opinion in Cardiology 2008, 23:105–110.
(1) Barlow JB, Pocock WA, Marchand P, Denny M. The significance of late systolic murmurs. Am Heart J 1963; 66:443–452.
(2) Criley JM, Lewis KB, Humphries JO, Ross RS. Prolapse of the mitral valve: clinical and cine-angiocardiographic findings. Br Heart J 1966; 28:488–496.
(3) Adams DH, Anyanwu AC, Rahmanian PB, et al. Large annuloplasty rings facilitate mitral valve repair in Barlow’s disease. Ann Thorac Surg 2006; 82:2096–2100.
(4) Sharma R, Mann J, Drummond L, et al. The evaluation of real-time 3-dimensional transthoracic echocardiography for the preoperative functional assessment of patients with mitral valve prolapse: a comparison with 2-dimensional transesophageal echocardiography. J Am Soc Echocardiogr 2007; 20:934– 940.
(5) Patel V, Hsiung MC, Nanda NC, et al. Usefulness of live/real time threedimensional transthoracic echocardiography in the identification of individual segment/scallop prolapse of the mitral valve. Echocardiography2006; 23:513–518. (6) Muller S, Muller L, Laufer G, et al. Comparison of three-dimensional imaging to transesophageal echocardiography for preoperative evaluation in mitral valve prolapse. Am J Cardiol 2006; 98:243–248.
A.3 Fibroelastic Deficiency
In contrast to Barlow’s disease, patients with mitral regurgitation due to fibroelastic deficiency have a lack of connective tissue as the pathological mechanism that triggers leaflet and chordal thinning and eventual chordal rupture1. Carpentier’s group characterized the typical findings in fibroelastic deficiency, noting that the chordal rupture resulting in mitral valve prolapse was often isolated, usually leading to prolapse of a single leaflet segment2.
Clinical Presentation
Figure 1: (a) Transesophageal echocardiography 4 chamber view shows single segment prolapse in a normal sized valve with isolated ruptured chord. The leaflets do not billow. (b) Valve analysis shows an otherwise normal-looking valve with a single chordal rupture to the P2 segment. (c) This valve was easily repaired with a limited triangular resection and ring annuloplasty, techniques that can be reproducibly performed by most experienced cardiac surgeons.
The typical patient with fibroelastic deficiency is over the age of 60 years, and does not have a long history of a heart murmur. Often asymptomatic until the time of chordal rupture, the patient often presents with palpitations or shortness of breath of limited duration. Patients may remain asymptomatic after chordal rupture, and present as a new-onset murmur or abnormal echocardiogram, but this is less frequent than in the setting of Barlow’s disease. Physical examination is remarkable for a holosystolic murmur, often harsh in nature.
Echocardiographic Findings
In contrast to Barlow’s disease, echocardiographic signatures of fibroelastic deficiency include normal or near-normal valve size, thin leaflets and chordae, and typically single segment prolapse, most commonly of the middle scallop of the posterior leaflet (P2) (Figure 1). The prolapsing segment may appear to be distended, thickened, and elongated, while the adjacent segments appear normal in height and consistency. Billowing of nonprolapsing segments is not observed, and bi-leaflet dysfunction is uncommon.
Surgical Considerations
In contradistinction to Barlow’s disease, patients with fibroelastic deficiency often present with minimal, as opposed to excess, tissue (Figure 1), so extensive leaflet resection or complex leaflet remodeling procedures are rarely indicated. In general, a limited quadrangular or triangular resection, or simple leaflet resuspension with a chordal transfer or artificial chord, is all that is required to correct leaflet prolapse. For posterior leaflet prolapse, although the prolapsing segment may look very abnormal, the remainder of the valve is relatively unaffected, so that the surgeon does not usually require advanced techniques to achieve a successful mitral valve reconstruction.
Table 1: Targeting referral pattern to optimize repair rates.
It should, however, be noted that ‘complex’ prolapse can occur in fibroelastic deficiency, usually involving an anterior leaflet segment or a commissural segment, and in this setting more advanced techniques and surgical skill are generally required to perform a successful reconstruction. Otherwise, simple fibroelastic deficiency with P2 prolapse is a condition associated with high repair rates in most experienced surgeons’ hands, and a virtually 100% repair rate within a reference center setting with a mitral repair subspecialist (Table 1).
Excerpted, with permission, Adams DH, Anyanwu AC. The cardiologist’s role in increasing the rate of mitral valve repair in degenerative disease. Current Opinion in Cardiology 2008, 23:105–110.
(1) Anyanwu AC, Adams DH. Etiologic Classification of Degenerative Mitral Valve Disease: Barlow’s Disease and Fibroelastic Deficiency. Semin Thorac Cardiovasc Surg 2007; 19:90–96.
(2) Carpentier A, Chauvaud S, Fabiani JN, et al. Reconstructive surgery of mitral valve incompetence: ten-year appraisal. J Thorac Cardiovasc Surg 1980; 79:338–348.
Numerous studies that have compared long term-survival of patients undergoing mitral valve repair or replacement have consistently shown a survival benefit with mitral valve repair. The ‘repair rate’ is thus an important variable. The ideal repair technique should be applicable to over 90% of cases. Repair rate statistics are not integral to the technique and vary from surgeon to surgeon. Unfortunately, most series do not include repair rates and prospective databases generally do not differentiate etiologies of mitral disease, such that it is not possible to accurately define repair rates for degenerative disease. We believe that the overall replacement rate in degenerative disease may be as high as 50%. In a review of United States practice in 1999 and 2000, 42.4% of patients having isolated mitral valve surgery for valve regurgitation had a valve repair (all etiologies of mitral disease)1. Similarly, in the United Kingdom, 35% of mitral procedures were repairs in 2000-20012. In the United Kingdom, more mechanical mitral valve replacements were performed than mitral repairs (ratio 6:5). We believe that as degenerative disease often occurs in young patients (who are the usual candidates for mechanical valves), and as the incidence of rheumatic disease has declined substantially in western countries, a considerable number of these mechanical mitral valve replacements are likely performed for degenerative disease. Indeed a review of contemporary mitral valve replacement literature shows substantial proportions of replacements for degenerative disease. For example, Bouchard and associates3 in a series examining outcomes of mitral valve replacement, include 213 replacements for degenerative disease over a ten-year period. In another recent study, Yun et al4 randomized 47 patients over two years to two forms of chordal sparing valve replacement; 31 of these patients had degenerative disease. Finally in a series of 154 bioprosthetic implants reported by Rizzoli et al, 34 were performed for degenerative disease5. Repair rates in large published series generally range from 85% to 90%, although most include historical patients from the 1980s. Our philosophy is that repair should be attempted in all degenerative valves. Using this approach we have achieved a 99.5% repair rate over a 4 year period. For mitral valve repair to be the standard of care for degenerative disease, it should be available and applicable to all patients. Certainly any surgeon performing surgery for asymptomatic degenerative disease should have > 95% repair rate for the lesion present, as mitral repair is the only therapy currently advisable in this group6. Current national repair rates, however, suggest that there remains a considerable body of surgical practice that has not embraced systematic repair of degenerative valves.
(1) Savage EB, Ferguson TB, Jr., DiSesa VJ. Use of mitral valve repair: analysis of contemporary United States experience reported to the Society of Thoracic Surgeons National Cardiac Database. Ann Thorac Surg 2003 March;75(3):820-5.
(2) Keogh BE, Kinsman R. Fifth National Adult Cardiac Surgical Database Report 2003. Henley-on-Thames: Dendrite; 2004.
(3) Bouchard D, Pellerin M, Carrier M et al. Results following valve replacement for ischemic mitral regurgitation.Can J Cardiol 2001 April;17(4):427-31.
(4) Yun KL, Sintek CF, Miller DC et al. Randomized trial comparing partial versus complete chordal-sparing mitral valve replacement: effects on left ventricular volume and function. J Thorac Cardiovasc Surg 2002 April;123(4):707-14.
(5) Rizzoli G, Bottio T, Vida V et al. Intermediate results of isolated mitral valve replacement with a Biocor porcine valve. J Thorac Cardiovasc Surg 2005 February;129(2):322-9.
(6) Hayek E, Gring CN, Griffin BP. Mitral valve prolapse. Lancet 2005 February 5;365(9458):507-18.
B.2 Long Term Survival
When interpreting data on long-term survival, it should be appreciated that available data refer to the outcomes of mitral repair and cardiac surgery as practiced 10 to 20 years previously1. Cardiac surgery has, however, since improved in several ways; for example, the widespread adoption of blood cardioplegia has likely reduced the ventricular damage during surgery which in turn will impact long-term survival (as left ventricular function is a major determinant of long-term survival). There is therefore no way of knowing the long-term survival outcomes of mitral valve surgery as currently practiced. Based on existing data, it appears that if surgery is undertaken before onset of symptoms and where left ventricular function is preserved, the life expectancy should be similar to that of the general population2, 3, 4. When significant symptoms of heart failure have developed (NYHA III – IV) before mitral valve surgery is undertaken, the long term survival is significantly reduced (Figure 1), regardless of the left ventricular function5. Similarly, patients with an impaired left ventricular ejection fraction at time of surgery have a reduced long-term survival (Figure 2).
Figure 1: Comparison of observed and expected survival after mitral valve surgery in patients in NYHA classes I-II (left) and classes III-IV (right). Numbers underneath indicate percentage of expected survival achieved.*
Figure 2: Survival after mitral valve surgery according to preoperative echocardiographic ejection fraction (EF). Numbers at bottom indicate patients at risk.**
(1) Adams DH, Anyanwu A. Pitfalls and limitations in measuring and interpreting the outcomes of mitral valve repair. J Thorac Cardiovasc Surg 2006 March;131(3):523-9.
(2) Enriquez-Sarano M. Timing of mitral valve surgery. Heart 2002 January;87(1):79-85.
(3) Mohty D, Orszulak TA, Schaff HV, Avierinos JF, Tajik JA, Enriquez-Sarano M. Very long-term survival and durability of mitral valve repair for mitral valve prolapse. Circulation 2001 September 18;104(12 Suppl 1):I1-I7.
(4) Braunberger E, Deloche A, Berrebi A et al. Very long-term results (more than 20 years) of valve repair with carpentier’s techniques in nonrheumatic mitral valve insufficiency. Circulation 2001 September 18;104(12 Suppl 1):I8-11.
(5) Tribouilloy CM, Enriquez-Sarano M, Schaff HV et al. Impact of preoperative symptoms on survival after surgical correction of organic mitral regurgitation: rationale for optimizing surgical indications. Circulation 1999 January 26;99(3):400-5.
(*) Modified from Tribouilloy CM, Enriquez-Sarano M, Schaff HV, et al: Impact of preoperative symptoms on survival after surgical correction of organic mitral regurgitation: rationale for optimizing surgical indications.Circulation 99 (3):400-5, 1999. Lippincott Williams & Wilkins
(**) Modified from Enriquez-Sarano M, Tajik AJ, Schaff HV, et al: Echocardiographic prediction of survival after surgical correction of organic mitral regurgitation. Circulation; 90(2):830-7, 1994. Lippincott Williams & Wilkins
B.3 Failures and Re-operations
Figure 1: Outcome after mitral valve repair. A,freedom from reoperation in patients with posterior, anterior and bileaflet prolapse. B,freedom from recurrent moderate (3+) or severe (4+) MR according to prolapsing leaflet. AL, anterior leaflet, PL, posterior leaflet, BL, bileaflet prolapse.*
Failure of repair, defined by recurrence of moderate or severe mitral regurgitation, or re-operation for mitral regurgitation are principal endpoints to evaluate the long-term outcomes of mitral valve repair. Failure rates of mitral valve repair are determined principally by the original dysfunction (posterior leaflet, anterior leaflet and bi leaflet) and by repair technique. The longest term follow-up available is for conventional ‘Carpentier’ techniques. Braunberger and colleagues1reported in 2001 on the long term outcomes of 162 non-rheumatic patients (of whom 90% were degenerative) who underwent a Carpentier repair between 1970 and 1984. They observed that 97% of patients with posterior leaflet, 86% with anterior leaflet and 83% of patients with bileaflet prolapse were free of re-operation at 20 years (Figure 1a). They also found 74% were free from cardiac events at 20 years. The difference between freedom from reoperation and freedom from cardiac event rates, however highlights the limitations of re-operation rate as an outcome measure for mitral repair. Because the decision to undergo reoperation is physician and patient dependent, at least some of those patients with cardiac symptoms had recurrent mitral regurgitation, but never underwent reoperation. In the absence of echocardiographic follow-up, there is no way of quantifying the true long-term failure rate. David and colleagues2 also presented 20 year follow-up for patients (operated between 1981 and 2001) using a variety of repair techniques, including conventional Carpentier techniques and gortex neochordoplasty, and found 96%, 88% and 94% freedom from re-operation rates at 12 years for posterior, anterior and bileaflet prolapse respectively. They also reported on freedom from moderate or severe mitral regurgitation – 80%, 65% and 67% respectively at 12 years (Figure 1b) – however, follow-up echocardiographic data was available for only half of the patients. The lack of systematic echocardiographic follow-up is the major limiting factor in determining the true durability of all mitral repair techniques3; most series have focused on survival and re-operation rates which may not necessarily be reflective of the durability of repair.
Figure 2: Freedom from recurrent mitral regurgitation after mitral valve repair. Kaplan-Meier estimates of freedom from non-trivial MR (MR>1/4) and failing repair (MR>2/4). A linearized recurrence rate per year of 8.3% is found for MR grade >1/4. The rate grade >2/4 is 3.4%.**
The most complete and elaborate follow-up for mitral repair in contemporary literature is probably the series of Flameng and associates4 who report a series of 242 consecutive mitral repairs with serial follow-up echocardiography done at 6 month intervals. They found a freedom from moderate or severe mitral regurgitation of 71% at 7 years and found that new recurrent mitral regurgitation appeared at a rate of 3.7% per year (Figure 2). The data of Flameng and colleagues4 suggest that durability of many mitral repairs is limited; the linear recurrence rate implies that recurrent mitral regurgitation is likely a reflection of progression of underlying valve disease. This hypothesis is supported by data from mitral re-operations after previous repair, as the previous repairs are found to be intact in two-thirds of patients, with recurrent regurgitation usually due to new valve lesions (chordal rupture, fibrosis, calcification, leaflet perforation)5. Technical failure can be a major cause of recurrence, particularly with early failures6, but should be minimal in experienced hands. Some surgical factors that predispose to recurrence of mitral regurgitation include the non-use of an annuloplasty ring, and the technique of chordal shortening.
The edge-to-edge technique is a relatively new repair strategy with limited follow-up compared to Carpentier techniques. One large published series from De Bonis and colleagues7 included 133 patients, followed for a median of 3 years, in whom anterior leaflet prolapse was treated with the edge-to-edge technique; they estimated a 10 year freedom from re-operation of 96.5%, but do not include data that allow computation of the freedom from mitral regurgitation rate.
(1) Braunberger E, Deloche A, Berrebi A et al. Very long-term results (more than 20 years) of valve repair with carpentier’s techniques in nonrheumatic mitral valve insufficiency. Circulation 2001 September 18;104(12 Suppl 1):I8-11.
(2) David TE, Ivanov J, Armstrong S, Christie D, Rakowski H. A comparison of outcomes of mitral valve repair for degenerative disease with posterior, anterior, and bileaflet prolapse. J Thorac Cardiovasc Surg 2005 November;130(5):1242-9.
(3) Adams DH, Anyanwu A. Pitfalls and limitations in measuring and interpreting the outcomes of mitral valve repair. J Thorac Cardiovasc Surg 2006 March;131(3):523-9.
(4) Flameng W, Herijgers P, Bogaerts K. Recurrence of mitral valve regurgitation after mitral valve repair in degenerative valve disease. Circulation 2003 April 1;107(12):1609-13.
(5) Cerfolio RJ, Orzulak TA, Pluth JR, Harmsen WS, Schaff HV. Reoperation after valve repair for mitral regurgitation: early and intermediate results. J Thorac Cardiovasc Surg 1996 June;111(6):1177-83.
(6) Shekar PS, Couper GS, Cohn LH. Mitral valve re-repair. J Heart Valve Dis 2005 September;14(5):583-7.
(7) De BM, Lorusso R, Lapenna E et al. Similar long-term results of mitral valve repair for anterior compared with posterior leaflet prolapse. J Thorac Cardiovasc Surg 2006 February;131(2):364-70.
(*) Modified from A, Braunberger E, Deloche A, Berrebi A, et al: Very long-term results (more than 20 years) of valve repair with carpentier’s techniques in nonrheumatic mitral valve insufficiency. Circulation 104(12 Suppl 1):I8-11 2001 Lippincott Williams & Wilkins and B, Reprinted from J Thorac Cardiovasc Surg 130(5), David TE, Ivanov J, Armstrong S, et al, A comparison of outcomes of mitral valve repair for degenerative disease with posterior, anterior, and bileaflet prolapse, 1242-9, Copyright 2005, with permission from the American Association for Thoracic Surgery.
(**) Modified from Flameng W, Herijgers P, Bogaerts K: Recurrence of mitral valve regurgitation after mitral valve repair in degenerative valve disease. Circulation 107(12):1609-13 2003. Lippincott Williams & Wilkins
B.4 Operative Mortality and Morbidity
The operative mortality rate for mitral valve surgery has steadily declined over the past decade, with the current mortality rates reported to the Society of Thoracic Surgery Database in the region of 1.5% for mitral valve repair and 5.5% for mitral valve replacement. There is a suggestion that centers doing large numbers of repairs for degenerative mitral valve disease deliver especially low mortality. For example, David and colleagues1 had only five operative deaths in a series of 701 repairs over 20 years, De Bonis and associates2 reported 2 deaths in a series of 738 repairs over 13 years, while Gillinov and colleagues reported 3 deaths in 1072 repairs for degenerative disease over a-12 year period3. Performing a tricuspid repair at time of mitral valve repair does not appear to increase mortality risk4, but mortality rises to above 3% with concomitant coronary artery bypass surgery5. Complications rates are low for elective mitral valve repair for degenerative valve disease. In our series of 67 consecutive Barlow patients we observed one patient with mediastinitis, one re-operation for bleeding and no strokes6. Major neurological complications should be uncommon in the 1% range, although there are recent data suggesting that patients having surgery via minimally invasive approaches may have a higher incidence of stroke7. Meticulous myocardial preservation is imperative to obtaining good results as the period of aortic clamping is lengthy for complex repairs (in our Barlow’s series we had a mean cardiopulmonary bypass time of 191 minutes)6.
(1) David TE, Ivanov J, Armstrong S, Christie D, Rakowski H. A comparison of outcomes of mitral valve repair for degenerative disease with posterior, anterior, and bileaflet prolapse. J Thorac Cardiovasc Surg 2005 November;130(5):1242-9.
(2) De BM, Lorusso R, Lapenna E et al. Similar long-term results of mitral valve repair for anterior compared with posterior leaflet prolapse. J Thorac Cardiovasc Surg 2006 February;131(2):364-70.
(3) Gillinov AM, Cosgrove DM, Blackstone EH et al. Durability of mitral valve repair for degenerative disease. J Thorac Cardiovasc Surg 1998 November;116(5):734-43.
(4) Dreyfus GD, Corbi PJ, Chan KM, Bahrami T. Secondary tricuspid regurgitation or dilatation: which should be the criteria for surgical repair? Ann Thorac Surg 2005 January;79(1):127-32.
(5) Gillinov AM, Blackstone EH, Rajeswaran J et al. Ischemic versus degenerative mitral regurgitation: does etiology affect survival? Ann Thorac Surg 2005 September;80(3):811-9.
(6) Adams DH, Anyanwu A, Rahmanian PB, Abascal V, Salzberg SP, Filsoufi F. Larger Annuloplasty Rings Facilitate Mitral Valve Repair in Barlow’s Syndrome. Ann Thorac Surg. 2006;82:2096-2101.
(7) Cheema FH, Martens TP, Duong JK et al. Comparison of Minimally Invasive Versus standard Approach to Mitral Valve Surgery: Results from an Audited State-Wide mandatory Database. Ann Thorac Surg. In press 2006.
Most complex mitral valve repair surgery can be performed through a 4 inch sternotomy.
Our Minimally Invasive Heart Surgery Center offers minimally invasive heart valve surgery to selected patients. Not all patients are suitable for minimally invasive surgery. Patients who require additional cardiac procedures like coronary artery bypass surgery, elderly patients, patients with very diseased arteries, and patients with a very weakly contracting heart will not be suitable for this approach. Our paramount objective is to ensure a good valve repair, with no residual leakage, at a low operative risk.Our surgeons will only perform a repair through a small incision when they believe they can do a good quality valve repair at a low risk to the patient; if the valve disease is complicated (as assessed by the echocardiogram) then we recommend a full incision as we believe a larger scar is preferable to an imperfect repair.
Ask the surgeon if this is an option for you.
Different Approaches to Minimally Invasive Heart Surgery
Dr. David Adams and Dr. Ani Anyanwu use special instruments to perform minimally invasive heart valve surgery.
The term “minimally invasive surgery” covers a spectrum of approaches. The goal is to perform surgery through a smaller incision without compromising the safety and long-term results of conventional mitral valve repair. The advantage of a small incision is mainly cosmetic (the scars are smaller and less visible). In some patients, the pain after surgery may be reduced and recovery from surgery is faster when surgery is done through a smaller incision. Operating through small incisions is however more technically demanding and in some cases could reduce the safety of the procedure. This page describes the various incisions, and you can read more about the associated benefits and disadvantages of each.
Lower Sternotomy
Dr. David Adams with Mary D., five weeks after surgery, whose minimally invasive valve repair was performed with a sternotomy.
In this approach the surgeon makes a 4 inch incision over the lower aspect of the midline of the chest and divides only the lower portion of the breast bone to gain access to the valve. This limits the actual amount of opening, and thus chest wall trauma. Through this incision we can easily access the heart and all the major vessels and can perform most complex mitral valve repairs along with aortic valve replacement or coronary artery bypass grafting. This incision has the advantage that if the surgeon encounters problems, he or she can easily extend the incision and divide the remaining breast-bone and convert to the standard approach. When fully healed the lower sternotomy scar is concealed by clothing, even when the patient wears low-necked clothing. In some women the scar is well concealed by their brassiere. It is the most flexible approach to the heart, and it is the approach we use in most patients.
Mini-Thoracotomy
Mitral valve surgery can be carried out through a 2-3 inch incision, usually under the right breast, which allows the surgical team to see and work on the mitral valve directly. The patient is placed on the heart-lung machine either through the same chest incision or through the vessels in the groin via a 1 inch incision. Durable, simple and more complex mitral repairs can be performed, eliminating mitral regurgitation in a wide range of patients.
Thoracotomy
Dr. David Adams shows a thoracotomy incision from a minimally invasive heart valve repair, eight days after surgery.
In this approach the surgeon makes a 4 to 6 inch incision in the right side (instead of middle) of the chest and gains access to the heart by going through the ribs. Some women prefer this incision because the scar may be placed underneath the breast crease and is therefore largely concealed. Access to the heart may be difficult in some cases making it more difficult to achieve a perfect repair.
Low Skin Incisions
Patients who are concerned about cosmesis, but who are not suitable for minimally invasive surgery, can request a low incision. The surgeon can make the standard skin incision start an inch lower and yet perform full division of the breastbone. The scar will therefore not be visible when wearing normal clothing. Patients who cannot have a minimally invasive operation, but who are concerned about the scar, can also request the services of our plastic surgeon to cosmetically close the incision.
Robotic Surgery and Endoscopic Surgery
In these approaches the surgeon performs the operation through several mini-incisions or “port sites”, the largest being about 2 inches. Robotic mitral valve repair is performed using the assistance of a ‘robot’ and specially designed instruments to perform the operation. The surgeon sits at a console and controls the instruments which are mounted on the arms of a robot by another surgeon. Endoscopic mitral valve repair is performed using long instruments placed through the port sites. The patient is placed on the heart-lung machine via blood vessels in the groin. In both cases, the surgeon uses video cameras to see inside the chest cavity.
Although cosmetically superior, these approaches limit the complexity of repair that can be undertaken by the surgeon, and in some cases may compromise on the quality of repair. For this reason, we do not offer these two approaches at Mount Sinai as we cannot guarantee the same high standards of mitral valve repair as we can with other approaches.
B. Non-surgical Management
Asymptomatic mitral regurgitation and
Medical management according to the effective regurgitant orifice (ERO)
Figure 1: Cardiac events among patients with asymptomatic mitral regurgitation and medical management according to the effective regurgitant orifice (ERO). Kaplan-Meier estimates of means ± standard deviation. Cardiac events were defined as death due cardiac causes, congestive heart failure, or new onset of atrial fibrillation.*
As current existing guidelines do not recommend surgery for asymptomatic or mildy symptomatic patients1, there is a large cohort of patients with significant mitral regurgitation that do not undergo surgery, thus allowing for observational studies of outcomes in non-surgically treated cohorts. Additionally, before expanded application of mitral valve repair in the 1990s, cohorts of symptomatic patients with mitral valve prolapse were followed on medical therapy allowing determination of natural history of mitral regurgitation. Mitral valve prolapse with severe regurgitation reduces long-term survival irrespective of medical therapy. It appears that the prolapse itself is not the cause of mortality or morbidity (cardiac event rates are extremely low for the entire population with prolapse), but it is severe regurgitation and consequent left ventricular dilatation that results in morbidity2, 3. Heart failure, arrhythmia, endocarditis and stroke are the leading causes of death. Enriquez-Sarano and colleagues have performed analyses to define which group of patients with mitral regurgitation are at greatest risk of cardiac events4, 5, 6. Notably, when considering asymptomatic patients, the greater the severity of mitral regurgitation (preferably determined by quantitative echocardiography), the higher the frequency of cardiac events irrespective of a normal ventricular function (Figure 1). Other risk factors for cardiovascular morbidity include atrial fibrillation, left atrial enlargement, age > 50 years and thickening of mitral leaflets7 – presence of these factors implies a reduced life expectancy if mitral regurgitation is uncorrected. Current evidence from surgical cohorts, suggests that mitral valve repair (assuming an operative mortality below 1%) yields a better outcome (survival and freedom from cardiac events) compared to the outcomes observed in non-surgically treated patients with severe regurgitation. For example mitral valve repair in patients with good ventricular function has a long term survival similar to expected survival in age matched cohorts5, 8, 9, whereas long term follow-up of patients with mitral valve prolapse treated medically shows a reduced survival compared to expected survival10 (Figure 2).
Figure 2: Long-term survival with medical treatment compared with expected durations of survival for patients with mitral regurgitation due to flailing leaflets. Kaplan-Meier curve of survival.**
It should be emphasized that the alternative to surgical therapy is, strictly speaking, not medical therapy, but observation, as there are no pharmacological options for treatment of severe mitral regurgitation. Data supporting the role of any medical treatment – particularly vasodilators – in the management of severe regurgitation due to degenerative mitral valve disease is scant11. Indeed it has been suggested that vasodilator therapy can lead to paradoxical worsening in mitral regurgitation by shifting the prolapse earlier in the cardiac cycle12. Vasodilator therapy can also mask left ventricular dysfunction and result in (potentially deleterious) delay to mitral valve surgery. According to current guidelines, there is little role for pharmacological treatment in the management of severe mitral regurgitation1.
Stem Cell Therapy for Coronary Artery Disease (CAD)
Author and Curator: Larry H. Bernstein, MD, FCAP
and
Curator: Aviva Lev-Ari, PhD, RN
There is great interest and future promise for stem cell therapy in ischemic heart disease. This is another report for the active work in cardiology with stem cell therapy by MA Gaballa and associates at University of Arizona.
Stem Cell Therapy for Coronary Heart Disease
Julia N. E. Sunkomat and Mohamed A. Gaballa
The University ofArizona Sarver Heart Center, Section of Cardiology, Tucson, Ar
Cardiovascular Drug Reviews 2003: 21(4): 327–342
Coronary artery disease (CAD) remains the leading cause of death in the Western world. The high impact of its main sequelae, acute myocardial infarction and congestive heart failure (CHF), on the quality of life of patients and the cost of health care drives the search for new therapies. The recent finding that
stem cells contribute to neovascularization and possibly improve cardiac function after myocardial infarction makes stem cell therapy the most highly active research area in cardiology. Although the concept of stem cell therapy may revolutionize heart failure treatment, several obstacles need to be addressed. To name a few:
Which patient population should be considered for stem cell therapy?
What type of stem cell should be used?
What is the best route for cell delivery?
What is the optimum number of cells that should be used to achieve functional effects?
Is stem cell therapy safer and more effective than conventional therapies?
The published studies vary significantly in design, making it difficult to draw conclusions on the efficacy of this treatment. For example, different models of
ischemia,
species of donors and recipients,
techniques of cell delivery,
cell types,
cell numbers and
timing of the experiments
have been used. However, these studies highlight the landmark concept that stem cell therapy may play a major role in treating cardiovascular diseasesin the near future. It should be noted that stem cell therapy is not limited to the treatment of ischemic cardiac disease.
Stem cells could be used as vehicle for gene therapy and eliminate the use of viral vectors. Finally, stem cell therapy may be combined with pharmacological, surgical, and interventional therapy to improve outcome. Here we attempt a systematic overview of the science of stem cells and their effects when transplanted into ischemic myocardium.
INTRODUCTION
Background
Congestive heart failure (CHF) is the leading discharge diagnosis in patients over the age of 65 with estimates of $24 billion spent on health care in the US (1,11). The number one cause of CHF is coronary artery diseases (CAD). Coronary care units, reperfusion therapy (lytic and percutaneous coronary intervention) and medical therapy with anti-platelet agents, statins, ACE-inhibitors and â-adrenoceptor antagonists all significantly reduce morbidity and mortality of CAD and CHF (9), but it is very difficult to regenerate new viable myocardium and new blood vessels.
Identification of circulating endothelial progenitor cells in peripheral blood that incorporated into foci of neovascularization in hindlimb ischemia (4) and the successful engraftment of embryonic stem cells into myocardium of adult dystrophic mice (31) introduced a new therapeutic strategy to the field of cardiovascular diseases: tissue regeneration. This approach is supported by the discovery of primitive cells of extracardiac origin in cardiac tissues after sex-mismatched transplants suggesting that an endogenous repair mechanism may exist in the heart (35,45,54). The number of recruited cells varied significantly from 0 (19) to 18% (54), but the natural course of ischemic cardiomyopathy implies that cell recruitment for tissue repair in most cases is insufficient to prevent heart failure. Therefore, investigational efforts are geared towards
augmenting the number of multipotent stem cells and endothelial and myocardial progenitor cells at the site of ischemia to induce clinically significant angiogenesis and potentially myogenesis.
Stem and Progenitor Cells
Stem cells are defined by their ability to give rise to identical stem cells and progenitor cells that continue to differentiate into a specific tissue cell phenotype (23,33). The potential of mammalian stem cells varies with stage of development and age (Table 1).
In mammals, the fertilized oocyte and blastomere cells of embryos of the two to eight cell stage can generate a complete organism when implanted into the uterus; they are calledtotipotent stem cells. After the blastocyst stage, embryonic stem cells retain the ability to differentiate into all cell types, but
cannot generate a complete organism and thus are denoted pluripotent stem cells.
Other examples of pluripotent stem cells are embryonic germ cells that are derived from the gonadal ridge of aborted embryos and embryonic carcinoma cells that are found in gonadal tumors (teratocarcinomas) (23,33). Both these cell types can also differentiate into cells of all three germ layers, but are not as well investigated as embryonic stem cells.
It is well established that embryonic stem cells can differentiate into cardiomyocytes (7,10,13,14,31,37,76), endothelial cells (55), and smooth muscle cells (5,22,78) in vitro, but it is unclear whether
pure populations of embryonic stem cell-derived cardiomyocytes can integrate and function appropriately in the heart after transplantation.
one study reported arrhythmogenic potential of embryonic stem cell-derived cardiomyocytesin vitro (80).
Adult somatic stem cells are cells that have already committed to one of the three germ layers: endoderm, ectoderm, or mesoderm (76). While embryonic stem cells are defined by their origin (the inner cell mass of the blastocyst), the origin of adult stem cells in mature tissues is still unknown. The primary role of adult stem cells in a living organism is thought to be maintaining and repairing the tissue in which they reside. They are the source of more identical stem cells and cells with a progressively more distinct phenotype of specialized tissue cells (progenitor and precursor cells) (Fig. 1). Until recently adult stem cells were thought to be lineage-specific, meaning that they can only differentiate into the cell-type of their original tissue. This concept has now been challenged with the discovery of multipotent stem and progenitor cells (26, 50, 51).
The presence of multipotent stem and progenitor cells in adult mammals has vast implications on the availability of stem cells to research and clinical medicine. Recent publications, however, have questioned whether the adaptation of a phenotype in those dogma-challenging studies is really a result of trans-differentiation or rather a result of cell and nuclear fusion (60,68,75,79). Spontaneous fusion between mammalian cells was first reported in 1961 (8), but how frequently fusion occurs and whether it occurs in vivo is not clear.
The bone marrow is a known source of stem cells. Hematopoietic stem cells are frequently used in the field of hematology. Surface receptors are used to differentiate hematopoietic stem and progenitor cells from mature cells. For example, virtually all
hematopoietic stem and progenitor cells express the CD34+ glycoprotein antigen on their cell membrane (73),
though a small proportion of primitive cells have been shown to be CD34 negative (58).
The function of the CD34+ receptor is not yet fully understood. It has been suggested that it may act as a regulator of hematopoietic cell adhesion in the bone marrow microenvironment. It also appears to be involved in the maintenance of the hematopoietic stem/progenitor cell phenotype and function (16,21). The frequency of immature CD34+ cellsin peripheral circulation diminishes with age.
It is the highest (up to 11%) in utero (69) and decreases to 1% of nucleated cells in term cord blood (63).
This equals the percentage of CD34+ cells in adult bone marrow.
The number of circulating stem cells in adult peripheral blood is even lower at 0.1% of nucleated cells.
Since hematopoietic stem cells have been identified as endothelial progenitor cells (29,30,32) their low density in adult bone marrow and blood could explain the inadequacy of endogenous recruitment of cells to injured organs such as an ischemic heart. The bone marrow is also home to another stem cell population the so-called mesenchymal stem cells. These may constitute a subset of the bone marrow stromal cells (2,43). Bone marrow stromal cells are a mixed cell population that generates
bone,
cartilage,
fat,
connective tissue, and
reticular network that supports cell formation (23).
Mesenchymal stem cells have been described as multipotent(51,52) and as a source of myocardial progenitor cells(41,59). They are, however, much less defined than the hematopoietic stem cells and a characteristic antigen constellation has not yet been identified (44).
Another example of an adult tissue containing stem cells is the skeletal muscle. The cells responsible for renewal and growth of the skeletal muscle are called satellite cells or myoblasts and are located between the sarcolemma and the basal lamina of the muscle fiber(5). Since skeletal muscle and cardiac muscle share similar characteristics such as they both are striated muscle cells, satellite cells are considered good candidates for the repair of damaged myocardiumand have been extensively studied (20,25,38–40,48,56, 64–67). Myoblasts are particularly attractive, because they can be autotransplanted, so that issues of donor availability, ethics, tumorigenesis and immunological compatibility can be avoided. They also have been shown to have a high growth potential in vitro and a strong resistance to ischemia in vivo(20). On the down side
they may have more arrhythmogenic potential when transplanted into myocardium than bone marrow or peripheral blood derived stem cells and progenitor cells (40).
Isolation of Cells Prior to Transplantation
Hematopoietic stem and progenitor cells are commonly identified by the expression of a profile of surface receptors (cell antigens). For example, human hematopoietic stem cells are defined as CD34+/CD59+/Thy-1+/CD38low/–/c-kit–/low/lin–, while mouse hema-topoietic stem cells are defined as CD34low/–/Sca-1+/Thy-1+/low/CD38+/c-kit+/lin– (23). Additional cell surface receptors have been identified as markers for subgroups of hema-topoietic stem cells with the ability to differentiate into non-hematopoetic tissues, such as endothelial cells (57,78). These can be specifically targeted by isolation methods that use the receptors for cell selection (positive selection with antibody coated magnetic beads or fluorescence-activated cell sorting, FACS). Other stem cell populations are identified by their behavior in cell culture (mesenchymal stem cells) or dye exclusion (SP cells). Finally, embryonic stem cells are isolated from the inner cell mass of the blastocyst and skeletal myoblasts are mechanically and enzymatically dissociated from an easily accessible skeletal muscle and expanded in cell culture.
FIG. 1. Maturation process of adult stem cells: with acquisition of a certain phenotype the cell gradually loses its self-renewal capability. (unable to transfer)
METHODICAL APPROACHES
FIG. 2. Intramyocardial injection:
the cells are injected directly into the myocardium through the epicardium. Usually a thoracotomy or sternotomy is required. Transendocardial injection: access can be gained from the arterial vasculature. Cells are injected through the endocardium into the myocardium, ideally after identifying the ischemic myocardium by perfusion studies and/or electromechanical mapping. Intracoronary injection: the coronary artery is accessed from the arterial vasculature. Stem cells are injected into the lumen of the coronary artery. Proximal washout is prevented by inflation of a balloon. Cells are then distributed through the capillary system. They eventually cross the endothelium and migrate towards ischemic areas.
The intracoronary delivery of stem cells (Fig. 2) and distribution through the coronary system has also been explored (6,62,74). This approach was pioneered by Robinson et al. (56), who demonstrated successful engraftment within the coronary distribution after intracoronary delivery of genetically labeled skeletal myoblasts.The risk of intracoronary injection is comparable to that of a coronary angiogram and percutaneous transluminal coronary angioplasty (PTCA) (62), which are safe and clinically well established.
RESULTS IN ANIMAL STUDIES AND HUMAN TRIALS
Differentiation into cardiomyocytes was observed after transplantation of embryonic stem cells, mesenchymal stem cells, lin–/c-kit+ and SP cells. The induction of angiogenesis was observed after transplantation of embryonic stem cells, mesenchymal stem cells, bone marrow-derived mononuclear cells, circulating endothelial progenitor cells, SP cells and lin–/c-kit+ cells.
The use of embryonic stem cells in ischemia was examined in two studies (42,43). These studies demonstrated that mice embryonic stem cells transplanted into rat myocardium exhibited cardiomyocyte phenotype at 6 weeks after transplantation. In addition, generation of myocardium and angiogenesis were observed at 32 weeks after allogenic transplantation in rats. In these two studies no arrhythmias or cardiac tumors were reported.
Several studies have shown retardation of LV remodeling and improvement of cardiac function after administration of bone marrow-derived mononuclear cells. For example, decreases in infarct size, and increase in ejection fraction (EF), and left ventricular (LV) time rate change of pressure (dP/dtmax) were observed after direct injection of bone marrow-derived mononuclear cells 60 min after ischemia in swine (28). In humans, intra-coronary delivery and transendocardial injection of mononuclear cells leads to a decrease in LV dimensions and improvement of cardiac function and perfusion (49,62). A decrease in end systolic volume (ESV) and an increase in EF as well as regional wall motion were observed following intracoronary administration of CD34+/CD45+ human circulating endothelial cells (6). Injection of circulating human CD34+/CD117+ cells into infarcted rat myocardium induced neoangiogenesis and improved cardiac function (32). This study suggests that the improvement in LV remodeling after infarction appears to be in part mediated by a decrease in apoptosis within the noninfarcted myocardium. Two other studies reported increased fractional shortening, improved regional wall motion and decreased left ventricular dimensions after transplantation of human CD34+ cells (29,30). Improved global left ventricular function and infarct perfusion was demonstrated after intramyo-cardial injection of autologous endothelial progenitor cells in humans (61).
DISCUSSION AND OUTLOOK
The idea of replacing damaged myocardium by healthy cardiac tissue is exciting and has received much attention in the medical field and the media. Therefore, it is important for the scientist to know what is established and what is based on premature conclusions. Currently, there are data from animal studies and human trials (Table 2). However, some of these data are not very concrete. For example,
many animal studies do not report the level of achieved neoangiogenesis and/or regeneration of myocardium.
In studies where the numbers of neovessels and new cardiomyocytes are specified, these numbers are often very low.
While these experiments confirm the concept that bone marrow and peripheral blood-derived stem and progenitor cells can differentiate into cardiomyocytes and endothelial cells when transplanted into ischemic myocardium, they also raise the question how effective this treatment is.
The results of the clinical trials that have been conducted are encouraging, but they need to be interpreted with caution. The common endpoints of these studies include left ventricular dimensions, perfusion, wall motion and hemodynamic function. While all studies report improvement after mononuclear cell, myoblast or endothelial progenitor cell transplantation, it is difficult to separate the effects of stem cell transplantation from the effects of the state-of-the art medical care that the patients typically received.
CONCLUSION
While the majority of studies demonstrate neoangiogenesis and some studies also show regeneration of myocardium after stem/progenitor cell transplantation, it remains unclear whether the currently achieved level of tissue regeneration is sufficient to affect clinical outcome. Long-term follow-up of patients that received stem/progenitor cells in clinical trials will provide important information on the potential risks of neoplasm and arrhythmias and, therefore, safety of this treatment. Ultimately, postmortem histological confirmation of scar tissue repair by transplanted cells and randomized placebo control trials with long-term follow-up are required to prove efficacy of this treatment.
REFERENCES (10)
1. American Heart Association Disease and Stroke Statistics-2003 Update, Dallas TX, American Heart Association; 2002 http://http://www.americanheart.org/downloadable/heart/10461207852142003HDSStatsBook.pdf
2. Arai A, Sheikh F, Agyeman K, et al. Lack of benefit from cytokine mobilized stem cell therapy for acute myocardial infarction in nonhuman primates. J Am Coll Cardiol 2003;41(Suppl 6A):371.
3. Asahara T, Masuda H, Takahashi T, et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 1999;85:221–228.
4. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275:964–967.
5. Asakura A, Seale P, Girgis-Gabardo A, Rudnicki M. Myogenic specification of side population cells in skeletal muscle. J Cell Biol 2002;159(1):123–134.
6. Assmus B, Schaechinger V, Teupe C, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation 2002;106:r53–r61.
7. Bader A, Al-Dubai H, Weitzer G. Leukemia inhibitory factor modulates cardiogenesis in embryoid bodies in opposite fashions. Circ Res 2000;86(7):787–794.
8. Barski G, Sorieul S, Cornefert F. “Hybrid” type cells in combined cultures of two different mammalian cell strains. J Natl Cancer Inst 1961;26:1269–1291.
9. Boersma E, Mercado N, Poldermans D, Gardien M, Vos J, Simoons M. Acute myocardial infarction. Lancet 2003;361:847–58.
10. Boheler K, Czyz J, Tweedie D, Yang H, Anisimov S, Wobus A. Differentiation of pluripotent embryonic stem cells into cardiomyocytes. Circ Res 2002;91:189–201.
Figure 1: Comparison of observed and expected survival after mitral valve surgery in patients in NYHA classes I-II (left) and classes III-IV (right). Numbers underneath indicate percentage of expected survival achieved.*
Figure 2: Survival after mitral valve surgery according to preoperative echocardiographic ejection fraction (EF). Numbers at bottom indicate patients at risk.**
Figure 2: Long-term survival with medical treatment compared with expected durations of survival for patients with mitral regurgitation due to flailing leaflets. Kaplan-Meier curve of survival.**
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