Posts Tagged ‘Biomedical Engineering’

Tumor Shrinking Triple Helices

Larry H. Bernstein, MD, FCAP, Curator



Tumor-Shrinking Triple-Helices

A braided structure and some adhesive hydrogel make therapeutic microRNAs both stable and sticky.

By Ruth Williams | April 1, 2016



MicroRNAs (miRs) are small, noncoding ribonucleic acids that control the translation of target messenger RNAs (mRNAs). Given their roles in development, differentiation, and other cellular processes, misregulation of miRs can contribute to diseases such as cancer. Indeed, “they are recognized as important modulators of cancer progression,” says Natalie Artzi of Harvard Medical School.

In addition to occasionally promoting cancer pathology, miRs also hold the potential to treat it—either by restoring levels of suppressed miRs, or by repressing overactive ones using antisense miRs (antagomiRs). While miRs are promising therapeutic molecules, says Daniel Siegwart of the University of Texas Southwestern Medical Center in Dallas, their use “is currently hindered by at least two issues: nucleic acid instability in vivo, and the development of effective delivery systems to transport miRs into tumor cells.”

Artzi and her team have now addressed both of these issues in one fell swoop. They first assembled two therapeutic miRs—one antagomiR and one that replaced a deficient miR—together with a third miR, a complement of the replacement strand, into triple-helix structures, which increased molecular stability without affecting function. They then complexed these helices with dendrimers—large synthetic branching polymer particles—and mixed these complexes with dextran aldehyde to form an adhesive hydrogel. The gel could then be applied directly to the surface of tumors to deliver the therapeutic miRs into cells with high efficiency.

In mice with induced breast tumors, the triple-helix–hydrogel approach led to dramatic tumor shrinkage and extended life span: the animals survived approximately one month longer than those treated with standard-of-care chemotherapy drugs. Because the RNA-hydrogel mixture must be applied directly to the tumor, the approach will not be suitable for all cancers. But one potential application, says Siegwart, is that “the hydrogel could be applied by a surgeon after performing bulk tumor removal…[and] might kill remaining tumor cells that would otherwise cause tumor recurrence.” (Nature Materials, http://dx.doi.org:/10.1038/NMAT4497, 2015)

STICKING IT TO TUMORS: To deliver therapeutic microRNAs (miRs) to tumors, braids of three microRNAs (miRs)—an antisense strand that blocks a miR overactive in cancer, a strand that replaces a deficient miR, and a stabilizing strand (1)—are added to a dendrimer (2) and mixed with a hydrogel scaffold (3). When researchers introduced the sticky gel onto mouse mammary tumors (4), the malignancies shrank and the animals lived longer (5)© GEORGE RETSECK; J.CONDE ET AL., NATURE MATERIALS


Nanoparticles Examples: gold particles, liposomes, peptide nucleic acids, or polymers Usually multiple injections Combining miRs with aptamers or antibodies can guide nanoparticles to target cells, but systemic delivery inevitably leads to some off-target dispersion. Multisite or blood cancers
RNA–triple-helix-hydrogel Dendrimer-dextran hydrogel One Adhesive hydrogel sticks miRs to tumor site with minimal dispersion to other tissues. Solid Tumors


Self-assembled RNA-triple-helix hydrogel scaffold for microRNA modulation in the tumour microenvironment

João CondeNuria OlivaMariana AtilanoHyun Seok Song & Natalie Artzi
Nature Materials15,353–363(2016)

The therapeutic potential of miRNA (miR) in cancer is limited by the lack of efficient delivery vehicles. Here, we show that a self-assembled dual-colour RNA-triple-helix structure comprising two miRNAs—a miR mimic (tumour suppressor miRNA) and an antagomiR (oncomiR inhibitor)—provides outstanding capability to synergistically abrogate tumours. Conjugation of RNA triple helices to dendrimers allows the formation of stable triplex nanoparticles, which form an RNA-triple-helix adhesive scaffold upon interaction with dextran aldehyde, the latter able to chemically interact and adhere to natural tissue amines in the tumour. We also show that the self-assembled RNA-triple-helix conjugates remain functional in vitro and in vivo, and that they lead to nearly 90% levels of tumour shrinkage two weeks post-gel implantation in a triple-negative breast cancer mouse model. Our findings suggest that the RNA-triple-helix hydrogels can be used as an efficient anticancer platform to locally modulate the expression of endogenous miRs in cancer.


Figure 1: Self-assembled RNA-triple-helix hydrogel nanoconjugates and scaffold for microRNA delivery.

Self-assembled RNA-triple-helix hydrogel nanoconjugates and scaffold for microRNA delivery.

a, Schematic showing the self-assembly process of three RNA strands to form a dual-colour RNA triple helix. The RNA triplex nanoparticles consist of stable two-pair FRET donor/quencher RNA oligonucleotides used for in vivo miRNA inhibit…


Figure 4: Proliferation, migration and survival of cancer cells as a function of RNA-triple-helix nanoparticles treatment.close

Proliferation, migration and survival of cancer cells as a function of RNA-triple-helix nanoparticles treatment.

a, miR-205 and miR-221 expression in breast cancer cells at 24, 48 and 72h of incubation (n = 3, statistical analysis performed with a two-tailed Students t-test, , P < 0.01). miRNA levels were normalized to the RNU6B reference gene


  1. Kasinski, A. L. & Slack, F. J. MicroRNAs en route to the clinic: Progress in validating and targeting microRNAs for cancer therapy. Nature Rev. Cancer 11, 849864 (2011).
  2. Li, Z. & Rana, T. M. Therapeutic targeting of microRNAs: Current status and future challenges. Nature Rev. Drug Discov. 13, 622638 (2014).
  3. Yin, H. et al. Non-viral vectors for gene-based therapy. Nature Rev. Genet. 15, 541555(2014).
  4. Conde, J., Edelman, E. R. & Artzi, N. Target-responsive DNA/RNA nanomaterials for microRNA sensing and inhibition: The jack-of-all-trades in cancer nanotheranostics? Adv. Drug Deliv. Rev. 81, 169183 (2015).
  5. Chen, Y. C., Gao, D. Y. & Huang, L. In vivo delivery of miRNAs for cancer therapy: Challenges and strategies. Adv. Drug Deliv. Rev. 81, 128141 (2015).
  6. Yin, P. T., Shah, B. P. & Lee, K. B. Combined magnetic nanoparticle-based microRNA and hyperthermia therapy to enhance apoptosis in brain cancer cells. Small 10, 41064112(2014).
  7. Hao, L. L., Patel, P. C., Alhasan, A. H., Giljohann, D. A. & Mirkin, C. A. Nucleic acid–gold nanoparticle conjugates as mimics of microRNA. Small 7, 31583162 (2011).
  8. Endo-Takahashi, Y. et al. Systemic delivery of miR-126 by miRNA-loaded bubble liposomes for the treatment of hindlimb ischemia. Sci. Rep. 4, 3883 (2014).
  9. Chen, Y. C., Zhu, X. D., Zhang, X. J., Liu, B. & Huang, L. Nanoparticles modified with tumor-targeting scFv deliver siRNA and miRNA for cancer therapy. Mol. Ther. 18, 16501656(2010).
  10. Anand, S. et al. MicroRNA-132-mediated loss of p120RasGAP activates the endothelium to facilitate pathological angiogenesis. Nature Med. 16, 909914 (2010).


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Pfizer Cambridge Collaborative Innovation Events: ‘The Role of Innovation Districts in Metropolitan Areas to Drive the Global an | Basecamp Business.

Reporter: Stephen J. Williams, Ph.D.

Monday, September 8 2014 5:30pm – 7:00pm Other Time Presented by:

Event Details:
Monday, September 8, 2014, 5:30-7PM EDT
Venue: Pfizer Cambridge Seminar Room (ground floor)
Location: Pfizer Inc., 610 Main Street, Cambridge, MA 02139 . Click here for a map to the location
(Corner of Portland and Albany street, Cambridge, MA 02139)
RSVP: To confirm your attendance please RSVP online through this website. This is an ONLINE REGISTRATION-ONLY event (there will not be registration at the door).

The Role of Innovation Districts in Metropolitan Areas to Drive the Global and Local Economy: Cambridge/Boston Case Study

Join Pfizer Cambridge at our new residence for a fascinating evening led by Vise-President and Founding Director, Bruce Katz of Brookings Institution, followed by a networking reception with key partners in our new Cambridge residence; Boston-Cambridge big pharma and biotech, members of the venture capital community, renowned researchers, advocacy groups and Pfizer Cambridge scientists and clinicians.

Boston/Cambridge is one of most prominent biomedical hubs in the world and known for its thriving economy. Recent advances in biomedical innovation and cutting-edge technologies have been a major factor in stimulating growth for the city. The close proximity of big pharma, biotech, academia and venture capital in Boston/Cambridge has particularly been crucial in fostering a culture ripe for such innovation.

Bruce Katz will shed light on the state of the local and global economy and the role innovation districts can play in accelerating therapies to patients. Katz will focus on the success Boston/Cambridge has had thus far in advancing biomedical discoveries as well as offer insights on the city’s future outlook.

The Brookings Institution is a nonprofit public policy organization based in Washington, D.C. Mr. Katz is Founding Director of the Brookings Metropolitan Policy Program, which aims to provide decision makers in the public, corporate, and civic sectors with policy ideas for improving the health and prosperity of cities and metropolitan areas.


5:30-6PM      Registration/Gathering (please arrive by no later than 5:45PM EDT with a
                       government issued ID to allow sufficient time for security check)

6-7PM            Welcoming remarks by Cambridge/Boston Site Head and Group Senior 
                       Vice-President WorldWide R&D, Dr. Jose-Carlos Gutierrez-Ramos

                        Keynote speaker: Bruce Katz, 
                        Founding Director Metropolitan Policy Program
                        Vice-president, The Brookings Institution

7-8PM             Open reception and Networking

8PM                 Event ends

This May, Pfizer Cambridge sites are integrating and relocating our research and development teams into our new local headquarters at 610 Main Street, Cambridge, MA 02139. The unified Cambridge presence represents the opportunity to interlace Pfizer’s R&D capability in the densest biomedical community in the world, to potentially expand our already existing collaborations and to embark on forging possible new connections. These events will further drive our collective mission and passion to deliver new medicines to patients in need. Our distinguished invited guests will include leaders in the Boston-Cambridge venture capital and biotech community, renowned researchers, advocacy groups and Pfizer Cambridge scientists and clinicians.  

Online registration:
If you are experiencing issues with online registration, please contact: Cambridge_site_head@pfizer.com  

Hashtags: #bcnet-PCCIE

Monday, September 8 2014 5:30pm – 7:00pm Other Time

Location: Pfizer Inc.
610 Main St
Cambridge, MA 02139

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Biomaterials Technology: Models of Tissue Engineering for Reperfusion and Implantable Devices for Revascularization

Author and Curator: Larry H Bernstein, MD, FACP


Curator: Aviva Lev-Ari, PhD, RN


This is the THIRD of a three part series on the evolution of vascular biology and the studies of the effects of biomaterials
in vascular reconstruction and on drug delivery, which has embraced a collaboration of cardiologists at Harvard Medical School , Affiliated Hospitals, and MIT,
requiring cardiovascular scientists at the PhD and MD level, physicists, and computational biologists working in concert, and
an exploration of the depth of the contributions by a distinguished physician, scientist, and thinker.

The FIRST part – Vascular Biology and Disease – covered the advances in the research on

Drug Eluting Stents: On MIT’s Edelman Lab’s Contributions to Vascular Biology and its Pioneering Research on DES

  • vascular biology,
  • signaling pathways,
  • drug diffusion across the endothelium and
  • the interactions with the underlying muscularis (media),
  • with additional considerations for type 2 diabetes mellitus.

The SECOND part – Stents and Drug Delivery – covered the

Vascular Repair: Stents and Biologically Active Implants

  • purposes,
  • properties and
  • evolution of stent technology with
  • the acquired knowledge of the pharmacodynamics of drug interactions and drug distribution.

In this THIRD part, on Problems and Promise of Biomaterials Technology, we cover the biomaterials used and the design of the cardiovascular devices, extension of uses, and opportunities for improvement

Biomaterials Technology: Tissue Engineering and Vascular Models –

Problems and Promise

We have thus far elaborated on developments in the last 15 years that have led to significant improvements in cardiovascular health.

First, there has been development of smaller sized catheters that can be introduced into

  • not only coronary arteries, but into the carotid and peripheral vasculature;

Second, there has been specific design of coated-stents that can be placed into an artery

  • for delivery of a therapeutic drug.

This began with a focus on restenosis, a serious problem after vascular repair, beginning
with the difficult problem of  control of heparin activity given intravenously, and was
extended to modifying the heparan-sulfate molecular structure

  • to diminish vascular endothelial hyperplasia,
  • concurrent with restriction of the anticoagulant activity.

Third, the ability to place stents with medicated biomaterials locally has extended to

  • the realm of chemotherapy, and we shall see where this progresses.

The Engineered Arterial Blood Flow Models

Biomedical engineers, in collaboration with physicians, biologists, chemists, physicists, and
mathematicians, have developed models to predict vascular repair by knowledge of

  • the impact of interventions on blood flow.

These models have become increasingly sophisticated and precise, and they propel us
toward optimization of cardiovascular therapeutics in general and personalizing treatments
for patients with cardiovascular disease. (1)
The science of vascular biology has been primarily stimulated by the clinical imperative to

  • combat complications that ensue from vascular interventions.

Thus, when a novel vascular biological finding or cardiovascular medical/surgical technique
is presented, we are required to ask the 2-fold question:

  • what have we learned about the biology of the blood vessel?
  • how might this knowledge be used to enhance clinical perspective and treatment?

The innovative method of engineering arterial conduits presented by Campbell et al. in
Circulation Research presents us with just such a challenge, and we deal with it’s biological and clinical ramifications.

Each of four pivotal studies in vascular tissue engineering has been an important advance
in the progression to a tissue-engineered blood vessel that can serve as a

  • living graft, responsive to the biological environment as
  • a self-renewing tissue with an inherent healing potential.
  • Weinberg and Bell taught us that a tissue-engineered graft could be constructed
  • and could be composed of human cells.

L’heureux et al demonstrated that the mechanical strength of such a material

  • derived in major part from the extracellular matrix and
  • production of matrix and integrity of cellular sheets
  • could be enhanced by alterations in culture conditions.

Niklason et al. noted that grafts are optimally formed

  • when incubated within environmental conditions that they will confront in vivo
  • or would have experienced if formed naturally.

Campbell et al. now demonstrate that it is possible to remove

  • the immune reaction and acute rejection that may follow cell-based grafting
  • by culturing tissues in the anticipated host and
  • address a fundamental issue of whether cell source or site of cell placement
  • dictates function after cell implantation.

It appears that the vascular matrix can be remodeled by the body according to the needs of the environment. It may
very well be that the ultimate configuration of autologous cell-based vascular graft need not be determined at
outset by the cells that comprise the device, but rather

  • by a dynamics that is established by environmental needs, wherein the body molds
  • tissue-engineered constructs to meet
    • local flow,
    • metabolic, and
    • inflammatory requirements.

In other words, cell source for tissue reconstruction may be secondary to
cell pliability to environmental influence.

Endothelial and smooth muscle cells from many, perhaps any,

  • vascular bed can be used to create new grafts and will then
  • achieve secondary function once in place in the artery.

The environmental remodeling observed after implantation

  • may modify limitations of grafts that are composed of nonvascular peritoneal cells whose initial structure
    is not either venous or arterial. (2)
  • The trilaminate vascular architecture provides biochemical regulation and mechanical integrity.
  • Yet regulatory control can be regained after injury without recapitulating tertiary structure.

Tissue-engineered (TE) endothelium controls repair even when

  • placed in the perivascular space of injured vessels.

It remains unclear from vascular repair studies whether endothelial implants recapitulate the vascular
epithelial lining
or expose injured tissues to endothelial cells (ECs) with unique healing potential because

  • ECs line the vascular epithelium and the vasa vasorum.

Authors examined this issue in a nonvascular tubular system, asking whether airway repair is controlled by

  • bronchial epithelial cells (EPs) or by
  • Endothelial Cells (ECs) of the perfusing bronchial vasculature.

Localized bronchial denuding injury

  • damaged epithelium, narrowed bronchial lumen, and led to
  • mesenchymal cell hyperplasia, hypervascularity, and inflammatory
  • cell infiltration. Peribronchial TE constructs embedded with

EPs or ECs limited airway injury, although optimum repair was obtained

  • when both cells were present in TE matrices.

EC and EP expression of

  • PGE2, TGF1, TGF2, GM-CSF, IL-8, MCP-1, and soluble VCAM-1
  • and ICAM-1 was altered by matrix embedding,

but expression was altered most significantly when both,

  • EC and EP,  cells were present simultaneously.

EPs may provide for functional control of organ injury and fibrous response, and

ECs may provide for preservation of tissue perfusion and the epithelium in particular.

Together the two cells

  • optimize functional restoration and healing, suggesting that
  • multiple cells of a tissue contribute to the differentiated biochemical function and repair
    of a tissue, but 
    need not assume
  • a fixed, ordered architectural relationship, as in intact tissues, to achieve these effects. (3)

Matrix-embedded Endothelial Cells (MEECs) Implants

The implantation of matrix-embedded endothelial cells (MEECs)

  • is considered to have therapeutic potential in controlling the vascular response to injury and
  • maintaining patency in arteriovenous anastomoses.

Authors considered the 3-dimensional microarchitecture of the tissue engineering scaffold to be
a key regulator of endothelial behavior in MEEC constructs.

Notably, Authors found that

  • ECs in porous collagen scaffold had a markedly altered cytoskeletal structure with oriented actin
    and rearranged focal adhesion proteins, in comparison to cells grown on 2D surfaces.

Examining the immunomodulatory capabilities of MEECs revealed, MEECs were able to reduce the recruitment
of monocytes
to an inflamed endothelial monolayer by 5-fold compared to EC on 2D surfaces.

An analysis of secreted factors from the cells revealed

  • an 8-fold lower release of Monocyte Chemotactic Protein-1 (MCP-1) from MEECs.

Differences between 3D and 2D cultured cells were abolished in the presence of

  • inhibitors to the focal adhesion associated signaling molecule Src, suggesting that
  • adhesion-mediated signaling is essential in controlling the potent immunomodulatory
    effects of MEEC. (4)

Cardiogenesis is regulated by a complex interplay between transcription factors. How do these interactions
regulate the transition from mesodermal precursors to cardiac progenitor cells (CPCs)?

Yin Yang 1 (YY1), a member of the GLI-Kruppel

  • family of DNA-binding zinc finger transcription factor (TF), can
  • activate or inhibit transcription in a context-dependent manner.

Bioinformatic-based Transcription Factor Genome-wide Sequencing Analysis

These investigators performed a bioinformatic-based transcription factor genome-wide sequencing analysis

  • binding  site analysis on upstream promoter regions of genes that are enriched in embryonic stem cell–derived CPCs
  • to identify novel regulators of mesodermal cardiac lineage

From 32 candidate transcription factors screened, they found that

  • Yin Yang 1 (YY1), a repressor of sarcomeric gene expression, is present in CPCs.

They uncovered the ability of YY1 to transcriptionally activate Nkx2.5,

  • Nkx2.5 as a key marker of early cardiogenic commitment.
  • YY1 regulates Nkx2.5 expression via a 2.1-kb cardiac-specific enhancer as demonstrated by in vitro
  1. luciferase-based assays,
  2. in vivo chromatin immunoprecipitation,
  3. and genome-wide sequencing analysis.

Furthermore, the ability of YY1 to activate Nkx2.5 expression depends on its cooperative interaction with Gata4.

Cardiac mesoderm–specific loss-of-function of YY1 resulted in early embryonic lethality.

This was corroborated in vitro by embryonic stem cell–based assays which showed the

  • overexpression of YY1 enhanced the cardiogenic differentiation of embryonic stem cells into CPCs.

The results indicate an essential and unexpected role for YY1

  • to promote cardiogenesis as a transcriptional activator of Nkx2.5
  • and other CPC-enriched genes. (5)

Proportional Hazards Models to Analyze First-onset of Major
Cardiovascular Disease Events

Various measures of arterial stiffness and wave reflection are considered to be cardiovascular risk markers.

Prior studies have not assessed relations of a comprehensive panel of stiffness measures to prognosis

Authors used Proportional Hazards Models to analyze first-onset of major cardiovascular disease events 

  • myocardial infarction,
  • unstable angina,
  • heart failure, or
  • stroke

In relation to arterial stiffness measured by

  • pulse wave velocity [PWV]
  • wave reflection
  • augmentation index [AI]
  • carotid-brachial pressure amplification [PPA]
  • and central pulse pressure [CPP]

in 2232 participants (mean age, 63 years; 58% women) in the Framingham Heart Study.

During median follow-up of 7.8 (range, 0.2 to 8.9) years,

  • 151 of 2232 participants (6.8%) experienced an event.

In multivariable models adjusted for

  • age,
  • sex,
  • systolic blood pressure,
  • use of antihypertensive therapy,
  • total and high-density lipoprotein cholesterol concentrations,
  • smoking, and
  • presence of diabetes mellitus,

Higher aortic PWV was associated with a 48% increase in

  • cardiovascular disease risk
    (95% confidence interval, 1.16 to 1.91 per SD; P0.002).

After PWV was added to a standard risk factor model,

  • integrated discrimination improvement was 0.7%
    (95% confidence interval, 0.05% to 1.3%; P < 0.05).

In contrast, AI, CPP, and PPA were not related to

  • cardiovascular disease outcomes in multivariable models.

(1) Higher aortic stiffness assessed by PWV is associated with

  • increased risk for a first cardiovascular event.

(2) Aortic PWV improves risk prediction when added to standard risk factors

  • and may represent a valuable biomarker of CVD risk in the community. (6)

1. Engineered arterial models to correlate blood flow to tissue biological response. J Martorell, P Santoma, JJ Molins,
AA Garcıa-Granada, JA Bea, et al.  Ann NY Acad Sci 2012: 1254:51–56. (Issue: Evolving Challenges in Promoting
Cardiovascular Health)    http://dx.doi.org/10.1111/j.1749-6632.2012.06518.x

2.  Vascular Tissue Engineering. Designer Arteries. Elazer R. Edelman. Circ Res. 1999; 85:1115-1117
http://www.circresaha.org  http://dx.doi.org/10.1161/01.RES.85.12

3.  Tissue-engineered endothelial and epithelial implants differentially and synergistically regulate airway repair.
BG Zani, K Kojima, CA Vacanti, and ER Edelman.   PNAS 13, 2008; 105(19):7046–7051.

4.  The role of scaffold microarchitecture in engineering endothelial cell immunomodulation.
L Indolfi, AB Baker, ER Edelman. Biomaterials 2012; http://dx.doi.org/10.1016/j.biomaterials.2012.06.052

5.  Essential and Unexpected Role of Yin Yang 1 to Promote Mesodermal Cardiac Differentiation. S Gregoire, R Karra,
D Passer, Marcus-André Deutsch, et al.  Circ Res. 2013;112:900-910. http://dx.doi.org/10.1161/CIRCRESAHA.113.259259

6.  Arterial Stiffness and Cardiovascular Events. The Framingham Heart Study.
GF Mitchell, Shih-Jen Hwang, RS Vasan, MG Larson, et al.  Circulation. 2010;121:505-511.

Cardiology Diagnosis of ACS and Stents – 2012

The Year in Cardiology 2012: Acute Coronary Syndromes.

Nick E.J. West      http://www.medscape.com/viewarticle/779039

The European Society of Cardiology (ESC) produced updated guidance on management of STEMI in 2012.
It also produced a third version of the Universal Definition of Myocardial Infarction.
The importance of early diagnosis is stressed, with first ECG in patients

  • with suspected STEMI recommended within 10 min of first medical contact (FMC)
  • and primary percutaneous coronary intervention (PPCI) for STEMI
  • ideally within 90 min (rated ‘acceptable’ out to a maximum of 120 min).

The guidance highlights the importance of collaborative networks

  • to facilitate achievement of such targets.
  • the importance of prompt assessment
  • management of atypical presentations not always considered under the umbrella of STEMI, including
    • left bundle branch block (LBBB),
    • paced rhythms, and
    • isolated ST-segment elevation in lead aVR,

especially when accompanied by symptoms consistent with myocardial ischaemia.

Therapeutic hypothermia is now recommended for

  • all resuscitated patients with STEMI complicated by cardiac arrest
  •  immediate coronary angiography with a view to follow-on PPCI
  • when the ECG demonstrates persistent ST-segment elevation.

In the light of recently published studies and meta-analyses,

  • including that of Kalesan et al., drug-eluting stents (DES) are
  • now routinely preferred to bare metal stents (BMS) in view of
  • the reduced need for repeat revascularization and the lack of
  • previously perceived hazard for stent thrombosis.

The more potent antiplatelet agents prasugrel and ticagrelor are also preferred

  • to clopidogrel for all STEMI cases, with duration of dual antiplatelet therapy (DAPT)
  • ideally for 1 year, but reduced to a strict
  • minimum of 6 months for patients receiving DES.

The Third Universal Definition of Myocardial Infarction was published
simultaneously with the STEMI guidance. This guideline endorses

  • cardiac troponin as the biomarker of choice to detect myocardial necrosis
  • with spontaneously occurring myocardial infarction (MI) defined as an
  • elevation above the 99th percentile upper reference value for the assay.

There is further development and clarification of MI in different settings

  • to allow standardization across trials and registries

in particular after revascularization procedures: after CABG with normal baseline troponin

  • MI is defined as a rise to a value 10 times greater than baseline in the first 48 h, and
  • a rise to 5 times greater than 99th percentile upper reference after PCI

in patients with a normal baseline level (or a 20% rise when troponin is elevated and stable or falling pre-procedure).

ACCF/AHA  updated guidance on the management of unstable angina/non-STEMI:

angiography with a view to revascularization

  • is now recommended within 12–24 h of presentation, with
  • DAPT pre-loading prior to PCI procedures also now advocated.

Ticagrelor and prasugrel are cited as acceptable alternatives to clopidogrel.
The maintenance dose of aspirin recommended for the majority of cases is 81 mg daily.
This guideline brings about transatlantic agreement in most areas.

Risk Stratification

Identification and appropriate triage of patients presenting to emergency departments
with acute chest pain remains a difficult dilemma:

  • many are low-risk and have a non-cardiac origin
  • a significant minority with coronary artery disease may not be picked up
    on clinical grounds even when accompanied by appropriate tests,

    • including ECG and biomarker estimation used in conjunction
    • with a clinical risk score (e.g. GRACE, TIMI).

As endorsed in ESC guidance, there has been increasing interest in

  • non-typical ECG patterns for the diagnosis of STEMI; although LBBB is
  • an accepted surrogate

Widimsky et al.  retrospectively analysed 6742 patients admitted to hospital with acute MI

  • in patients presenting with right bundle branch block, a blocked epicardial vessel was
  • more common (51.7 vs. 39.4%; P < 0.001) and incidence of both shock and mortality
  • comparable with LBBB (14.3 vs. 13.1%; P = NS; and 15.8 vs. 15.4%; P = NS, respectively).

Wong et al. demonstrated the importance of ST-elevation in lead aVR,

  • often viewed as indicative of left main stem occlusion, having increased mortality
  • in patients presenting with both inferior and anterior infarction.

Perhaps the most important data regarding the ECG in 2012 were also the most simple:

  • Antoni et al. highlighted a powerful and very simple method of risk stratification;
  •  heart rate measured on a 12-lead ECG at discharge after Primary PCI (PPCI) is an
  • independent predictor of mortality at 1 and 4 years of follow-up.

Patients with a discharge heart rate of ≥70 b.p.m. had a two-fold higher mortality at both follow-up
time points, with every increase of 5 b.p.m. in heart rate

  • equating to a 29% increase in mortality at 1 year and 24% at 5 years.

These findings have important implications for the optimization of patient therapies after MI (including the use of
rate-limiting agents such as beta-blockers, calcium channel-blockers, and ivabradine), although large randomized
trials are needed to confirm that

  • interventions to reduce heart rate will replicate the benefits observed in this study.


Figure 1.  Kaplan–Meier time-to-event plots for heart rate at discharge divided by quartiles and all-cause mortality
(A and C) and cardiovascular mortality (B and D) at 1-year (A and B) and 4-year (C and D) follow-up,
demonstrating relationship between discharge heart rate and mortality after PPCI for STEMI.
Modified from Antoni et al.

Coronary Intervention and Cardioprotection in Acute Coronary Syndromes

Microvascular obstruction during PCI for ACS/STEMI is associated with increased infarct size and adverse prognosis;
its pathophysiology is thought to be a combination of

  • mechanical distal embolization of thrombus and plaque constituents during PCI,  coupled with
  • enhanced constriction/hyperreactivity of the distal vascular bed.

The most novel Strategy to Reduce Infarct Size

is the use of a Bare Metal Stent (BMS) covered on its outer surface with a mesh micronet designed to
trap and hold potentially friable material that might embolize distally at the time of PCI.

The MASTER study randomized 433 STEMI patients to PPCI

  • with conventional BMS or DES at the operator’s discretion vs.
  • the novel MGuard stent (InspireMD, Tel Aviv, Israel);

the primary endpoint of complete ST-segment resolution was better

  • in patients receiving MGuard (57.85 vs. 44.7%; P = 0.008), as was
  • the achievement of TIMI grade 3 flow in the treated vessel (91.7 vs. 82.9%; P = 0.006).

Nevertheless, median ST-segment resolution did not differ

  • between treatment groups,
  • myocardial blush grade was no different, and
  • safety outcomes at 30 days (death, adverse events) as well as
  • overall MRI-determined infarct mass.

Higher TVR rates may accrue with a BMS platform when compared with

  • current-generation DES (as now endorsed for PPCI in ESC guidance).

In comparing the four studies in cardioprotection, there remains little to choose between strategies as evidenced by

  • the relatively minor differences between surrogate endpoints employed regardless of
  • therapeutic intervention chosen (Figure 2).


Figure 2.  Comparison of study endpoints for reduction in infarct size in STEMI.
Study endpoints listed on the x-axis. STR, ST-segment resolution; TIMI 3, thrombolysis in
myocardial infarction grade 3 antegrade flow; myocardial blush grade 2/3 (MBG 2/3).

Recent advances in

  • PCI equipment,
  • peri-procedural pharmacology,
  • technique, and safety, as well as
  • convergence of national guidance,

are leading to the point where

  • even in the highest risk patients such as those presenting with ACS, small improvements
  • may be difficult to discern despite large well-designed and -conducted studies.


  1. a. The Task Force on the management of ST-segment elevation acute myocardial infarction
    of the European Society of Cardiology. ESC guidelines for the management of acute
    myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J
    2012;33:2569–2619.  b. Management of acute myocardial infarction in patients presenting
    with ST-segment elevation. The Task Force on the Management of Acute Myocardial
    Infarction of the European Society of Cardiology.  Eur Heart J 2003; 24 (1): 28-66.
  2. ESC Guidelines for the management of acute coronary syndromes in patients presenting
    without persistent ST-segment elevation: The Task Force for the management of acute
    coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation
    of the European Society of Cardiology (ESC).  http://dx.doi.org/10.1093/eurheartj/ehr236
  3. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BS, White HD. The Writing Group on
    behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of
    Myocardial Infarction. Third universal definition of myocardial infarction.
    Eur Heart J 2012;33:2551–2567.  http://dx.doi.org/10.1093/eurheartj/ehm355
  4. Kalesan B, Pilgrim T, Heinimann K, Raber L, Stefanini GG, et al. Comparison of drug-eluting
    stents with bare metal stents in patients with ST-segment elevation myocardial infarction.
    Eur Heart 2012;33:977–987.
  5. Jneid H, Anderson JL, Wright RS, Adams CS, et al. 2012 ACCF/AHA Focused Update of the
    Guideline for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial
    Infraction (Updating the 2007 Guideline and Replacing the 2011 Focused Update). A Report
    of the American College of CardiologyFoundation/American Heart Association Task Force
    on Practice Guidelines. J Am Coll Cardiol 2012;60:645–681.
  6. Widimsky P, Rohác F, Stásek J, Kala P, Rokyta R, et al. Primary angioplasty in acute myocardial
    infarction with right bundle branch block: should new onset right bundle branch block be added
    to future guidelines as an indication for reperfusion therapy? Eur HeartJ 2012;33:86–95.
  7. Wong CK, Gao W, Stewart RA, French JK, and the HERO-2 Investigators. The prognostic meaning of
    the full spectrum of aVR ST-segment changes in acute myocardial infarction.
    Eur Heart J 2012;33:384–392.
  8. Antoni L, Boden H, Delgado V, Boersma E, et al. Relationship between discharge heart rate and mortality
    in patients after myocardial infarction treated with primary percutaneous coronary intervention.
    Eur Heart J 2012;33:96–102.
  9. Stone GW, Abizaid A, Silber S, Dizon JM, Merkely B, et al. Prospective, randomised, multicenter evaluation
    of a polyethylene terephthalate micronet mesh-covered stent (MGuard) in ST-segment elevation myocardial
    infarction. The MASTER Trial. J Am Coll Cardiol. doi:pii:S0735-1097(12)04506-8. 10.1016/j.jacc.2012.09.004. 
  10. Zhou C, Yao Y, Zheng Z, Gong J, Wang W, Hu S, Li L. Stenting technique, gender, and age are associated with
    cardioprotection by ischaemic postconditioning in primary coronary intervention: a systematic review of
    10 randomized trials. Eur Heart J 2012;33:3070–3077.

Resistant Hypertension.

Robert M. Carey.
Hypertension. 2013;61:746-750.  http://dx.doi.org/10.1161/HYPERTENSIONAHA.111.00601

Resistant hypertension is defined as failure to achieve goal blood pressure (BP) <140/90 mm Hg
(or <130/80 mm Hg in patients with diabetes mellitus or chronic kidney disease) in patients with

  • hypertension who are compliant with maximum tolerated doses of an appropriate antihypertensive drug regimen consisting of a minimum of 3 agents of different classes, including a diuretic.
  • Patients who meet the criteria for resistant hypertension but whose BP can be controlled on maximum tolerated
    doses of ≥4 antihypertensive agents are classified as having controlled resistant hypertension.

Although the number of failed antihypertensive drugs required for the classification of resistant hypertension is arbitrary,

  • this diagnosis identifies patients at high risk for having a potentially curable form of hypertension, and
  • those who may benefit from specific therapeutic approaches to lower BP.


The first portion of this document shows the impact that ER Edelman and his peers have had in the development
of interventional cardiology, and in carrying out studies to test, validate, or reject assumptions about the interaction of
biomaterials with

  • vascular and smooth muscle tissue in the repair of injured vessels, by
  1. trauma
  2. inflammatory injury
  3. stent placement.

In the second portion of this discussion, I introduce current views about complications in implanted devices, evolving
standards, and the current definitions of stable, unstable, and previously unclassified ACS risk.

Pushing Drug-Eluting Stents Into Uncharted Territory

Simpler Than You Think—More Complex Than You Imagine

Campbell Rogers, MD; Elazer R. Edelman, MD, PhD.  Circulation 2006; 113: 2262-2265.

Mechanical failure is a characteristic of a material or a device and not necessarily an indication of inadequacy. All devices
will fail under some specific stress. It is only failure at the lowest levels of stress that may represent inadequacy. Stress on
a material, for example, rises with strain until a critical load is exceeded, at which point the material fatigues and loses
mechanical integrity. Failure analysis, the science by which these conditions are rigorously defined, is an important
component of device design, development, and use. Once the transition point to failure is identified, material use can be
restricted to the zone of safety or modified so as to have this zone expanded. Just as the characterization of a material is
incomplete unless pushed to the limits of load bearing, characterization of an implantable device is incomplete unlesspreclinical and clinical environments test the limits of device functionality. It was in this light in 1999 that the Authors noted the impossibility of defining the functional limits of novel bare metal stents in head-to-head trials, which, by necessity, could only include lesions into which the predicate device (the Palmaz-Schatz stent, Cordis, Warren, NJ) could have be placed.

New School Percutaneous Interventions

Over the past 5 years, the number of percutaneous interventions has grown by 40%. This expansion derives from an
increased breadth of cases, as percutaneous interventions are now routinely performed in diabetic, small-vessel, multilesion,diffuse disease, and acute coronary syndrome settings. Contemporaneously, widespread adoption of drug-eluting stents has emboldened clinicians and provided greater security in the use of these devices in lesions or patients previously thought to

Head-to-head randomized trial data have accumulated so that analysis may demonstrate differences among drug-eluting stents. The playing field for prospective randomized trials could enhance the weight of evidence to unanswered questions about what underlying factors determine device failure.

Complexity Simplified

Drug-eluting stent “failure” can be defined operationally in the same way as material failure:

  • inadequate function in the setting of a given load or strain.

The inability to withstand stress may take many forms that can change over time. Failure may be manifest acutely as

  • the inability to deliver a stent to the desired location,
  • subacutely as stent thrombosis or
  • postprocedural myonecrosis, and later as
  • restenosis

“Simple lesions” are those in which few devices should fail;“Complex” lesions have a heightened risk of failure. To be of value, each scale of advancing complexity must provoke higher failure rates.  For any device may fail sooner than another along one such “complexity” scale and later along another. As advanced drug-eluting stent designs have enhanced deliverability and reduced restenosis rates, 7 randomized trials comparing directly the two Food and Drug Administration (FDA)-approved drug-eluting stents, Cypher (Cordis-Johnson and Johnson) and Taxus (Boston Scientific, Boston, Mass), have been reported.  These trials report a broad range of restenotic failure as evidenced by the need for revascularization. Across these trials, driven by a variety of factors, revascularization rates vary quite widely.

The clinical end point of target lesion revascularization (TLR) becomes

  • a single measure of device failure.

When the 7 trials are depicted in order of increasing TLR, the rate of failure increases more slowly with 1 device than
the other.  This gives two regression plots for Taxus vs Cypher with different slopes, as complexity increases, and the

  • separation between the failure rates of the two devices broadens plotted against “degree of complexity” assigned by the  slopes of the lines.

Finally, the correlation between TLR rates for Taxus and Cypher stents indicates that trial-specific events and conditions determined TLR (with a sharp slope of Taxus vs Cypher (r-sq = 0.85).  The ratio of TLR (the slope) wasgreater than 3, suggesting that although both devices are subject to increasing failure as complexity increases,

  • one device becomes ever-more likely than the other to fail when applied in settings with ever-higher TLR risk.

In other words, composite medical devices with a wide range of

  • structural,
  • geometric, and
  • pharmacological differences
    • can be shown to produce different clinical effects
    • as the environments in which they are tested become increasingly complex.

What the Individual Trials Cannot Tell Us

The progressive difference between the performances of the 2 FDA-approved drug-eluting stents as they are pushed into
more complex settings is precisely what one would anticipate from medical devices with different performance signatures.
Most randomized trials, even if they include high complexity, are unable to identify predictors of failure because of the low numbers of patients enrolled, and the problem gets worse as the number of subsets increase. Consequently, device development, and clinical practice, knowing which patient or lesion characteristics confer higher failure rates is critical.
This analysis has centered on restenosis. Other failure modes to be considered are

  • stent thrombosis,
  • postprocedural myonecrosis
  • late plaque rupture
  • vascular disease away from the site
  • heightened inflammatory reaction
    • are no less critical and may be determined by
    • completely different device or patient characteristics.

Well-executed registry or pooled data

It is in this light that the registry report of Kastrati et al. in the current issue of Circulation is of greatest value. There are
two ways in which well-executed registry or pooled data can be most complementary to randomized trials.

First, large numbers of patients provide a higher incidence of rare failure modes as well as allow more granular determination of lesion- or patient-specific predictors of failure (meta-analysis or better, combined data file). A pooled analysis of several head-to-head randomized bare metal stent trials allowed identification of clear risk factors for stent thrombosis that had eluded analysis of the individual (smaller) trials.

Second, registry or pooled data may incorporate a broader range of patient characteristics, allowing greater discrimination between devices. The report of Kastrati et al may fall into this category as well, as it includes “high risk” populations from several randomized trials. They report on more than 2000 lesions in 1845 patients treated with either Taxus or Cypher drug-eluting stents at two hospitals.  The study population is from a series of randomized trials comparing Taxus and Cypher stents.   Using multivariate analysis to identify what lesion and patient characteristics predict failure (restenosis), they identified risk factors that included

  • prior history of coronary bypass surgery
  • calcification
  • smaller vessel size
  • greater degree of prestent and poststent stenosis.

Use of a Cypher rather than Taxus stent was independently associated with lower restenosis risk.

An interesting negative finding was the absence of diabetes as a significant predictor, at odds with strong suggestions from several other analyses. A better understanding from preclinical or clinical studies of the effect of diabetic states on restenosis is critical.

Author’s opinion voiced:

This Author (LHB), considers the study underpowered to answer that question because of further partitioning with several variables. Pooled data with

  • rigorous ascertainment and
  • careful statistical methodology, taken
  • together with randomized trial data, open a door to device choice based on the knowledge that risk of failure (complexity) does vary, and
  • the higher the complexity, the greater the incremental benefit of choosing one device over another.

A decision algorithm is therefore possible, whereby multiple failure modes and risk factors are weighed, and

  • an optimum stent choice made which balances
  • safety and efficacy based on the totality of evidence, rather than anecdote and loose comparisons of disparate subgroups from individual trials.

Evaluating Clinical Trials

The subject of trial(s) is difficult… the aim and meaning of all the trials… is

  • to let people know what they ought to do or what they must believe

It was perhaps naïve to imagine that devices as different one from another as the two current FDA-approved drug-eluting
stents would produce identical clinical results. If so, it ought not to come as a surprise that head-to-head randomized trial
data from many different countries in complex settings are now indicating just how differently the 2 devices may perform.

Future trials should be designed and evaluated to examine why these differences exist. Trials residing
only in previous safety and complexity domains

  • are unlikely to offer deeper insights into
    1. device performance,
    2. patient care decisions, or
    3. discrimination of alternative therapies.

We look forward to more trials that will examine what we currently believe to be the limits of

  • drug-eluting stents and interventional cardiology and to

help define in simple terms differences

  • between complex devices applied to complex problems.

This 2009 article was an excellent demonstration of comparing two commonly used coated-stents, and then extending the argument to the need for more data to further delineated the factors that explain the differences they found. In the previous article, the SECOND in the three article series,  Stents and Drug Delivery

Vascular Repair: Stents and Biologically Active Implants

we concentrated on stents and drug delivery, and not on stent failure.  But the following article in J Control Release,

was published the following year, and is another example of this method of explanatory approach to the problem.

Lesion Complexity Determines Arterial Drug Distribution After Local Drug Delivery

AR Tzafriri,  N Vukmirovic, VB Kolachalama, I Astafieva, ER Edelman. J Control Release. 2010; 142(3): 332–338.
http://:dx. doi:.org/10.1016/j.jconrel.2009.11.007       PMCID: PMC2994187

Local drug delivery from endovascular stents has transformed how we treat coronary artery disease. Yet, few drugs are in fact effective when delivered from endovascular implants and those that possess a narrow therapeutic window. The width of this window is predicated to a great degree upon the extent of drug deposition and distribution through the arterial wall.

  • Drugs that are retained within the blood vessel are far more effective than those that are not.

Thus, for example, heparin regulates virtually every aspect of the vascular response to injury, but it is so soluble and diffusible that it simply cannot stay in the artery for more than minutes after release.

  • Heparin has no effect on intimal hyperplasia when eluted from a stent.
  • Paclitaxel and sirolimus in contradistinction are far smaller compounds with perhaps more narrow and specific effects than heparin.

These drugs bind tenaciously to tissue protein elements and specific intracellular targets and remain beneath stent struts long after release.

The clinical efficacy of paclitaxel and sirolimus at reducing coronary artery restenosis rates following elution from stents appears incontrovertible. Emerging clinical and preclinical data suggest that the benefit of the local release of these drugs is beset by significant complications, that rise with lesion complexity as

  • the native composition and layered ultrastructure of the native artery is more significantly disrupted.

Virmani and others have hypothesized that the attraction of lipophilic drugs like paclitaxel and sirolimus to fat should affect their retention within and effects upon atheromatous lesions.

Though stents are deployed in diseased arteries drug distribution has only been quantified in intact, non-diseased vessels.

Authors @ MIT, correlated steady-state arterial drug distribution with tissue ultrastructure and composition in abdominal aortae from atherosclerotic human autopsy specimens and rabbits

  • with lesions induced by dietary manipulation and controlled injury.

Drug and compositional metrics were quantified and correlated at a compartmental level, in each of the tunica layers, or at an intra-compartmental level. All images were processed to

  • eliminate backgrounds and artifacts, and
  • pixel values between thresholds were extracted for all zones of interest.

Specific algorithms analyzed each of the histo/immuno-stained arterial structures. Intra-compartmental analyses were

  • performed by sub-dividing arterial cross-sections into 2–64 equal sectors and
  • evaluating the pixel-average luminosity for each sector.

Linear regression of drug versus compositional luminosities asymptotically approached steady state after subdivision into 16 sectors. This system controlled delivered dose and removed the significant unpredictability in release that is imposed by variability

  • in stent position relative to the arterial wall,
  • inflation techniques and stent geometry.
As steady state tissue distribution results were obtained under constant source conditions, without washout by flowing blood,
  • they constitute upper bounds for arterial drug distribution
  • following transient modes of in vivo drug delivery wherein
  • only a fraction of the eluted dose is absorbed by the artery

Paclitaxel, everolimus, and sirolimus deposition in human aortae was maximal in the media and scaled inversely with lipid content.

Net tissue paclitaxel and everolimus levels were indistinguishable in mildly injured rabbit arteries independent of diet. Yet, serial sectioning of cryopreserved arterial segments demonstrated

  • a differential transmural deposition pattern that was amplified with disease and
  • correlated with expression of their intracellular targets, tubulin and FKBP-12.

Tubulin distribution and paclitaxel binding increased with

  • vascular injury and macrophage infiltration, and
  • were reduced with (reduced) lipid content.

Sirolimus analogues and their specific binding target FKBP-12 were less sensitive to alterations of diet
in mildly injured arteries, presumably reflecting a faster transient response of FKBP-12 to injury.

The idea that drug deposition after balloon inflation and stent implantation within diseased, atheromatous and sclerotic vessels tracks so precisely with specific tissue elements is

  • an important consideration of drug-eluting technologies and
  • may well require that we consider diseased rather than naïve tissues in preclinical evaluations.

Another publication in the same year reveals the immense analytical power used in understanding the complexities
of drug-eluting stents.

Luminal Flow Amplifies Stent-Based Drug Deposition in Arterial Bifurcations

Kolachalama VB, Levine EG, Edelman ER.    PLoS ONE 2009; 4(12): e8105.

Treatment of arterial bifurcation lesions using drug-eluting stents (DES) is now common clinical practice.
Arterial drug distribution patterns become challenging to analyze if the lesion involves more than a vessel
such as in the case of bifurcations.  As use extends to nonstraightforward lesions and complex geometries,
questions abound

  • regarding DES longevity and safety

Indeed, there is no consensus on best stent placement scenario, no understanding as to

  • whether DES will behave in bifurcations as they do in straight segments, and
  • whether drug from a main-branch (MB) stent can be deposited within a side-branch (SB).

It is not evident how to

  • efficiently determine the efficacy of local drug delivery and
  • quantify zones of excessive drug that are
  • harbingers of vascular toxicity and thrombosis,
  • and areas of depletion that are associated
  • with tissue overgrowth and
  • luminal re-narrowing.

Geometry modeling and governing equations

Authors @MIT constructed two-phase computational models of stent-deployed arterial bifurcations

  • simulating blood flow and drug transport to investigate the
  • factors modulating drug distribution when the main-branch (MB) was treated using a DES.

The framework for constructing physiologically realistic three dimensional computational models of single
and bifurcated arterial vessels was SolidWorks (Dassault Systemes) (Figs. 1A–1B, Movie S1). The geometry
generation algorithm allowed for controlled alteration of several parameters including

  • stent location
  • strut dimensions
  • stent-cell shape
  • lumen diameter to arterial tissue thickness ratio
  • lengths of the arterial branches
  • extent of stent apposition and
  • the bifurcation angle.

For the current study, equal lengths (2LS) were assumed for the proximal and distal sections of the MB from the bifurcation. The SB was constructed at an angle of 300. The inlet conditions were based on

  • mean blood flow and
  • diameter measurements

obtained from human left anterior descending coronary artery (LAD).

The diameter of the lumen (DMB) and thickness (TMB) for the MB were defined such that DMB=TMB~10 and

  • this ratio was also maintained for the SB.

Schematics of the computational models used for the study. A stent of length LS is placed at the upstream section of the arterial vessel in the (A) absence and in the (B) presence of a bifurcation, respectively.

  • Insets in (B) denote delta wing stent design (i),
  • strut thickness (d) (ii), and
  • the outlets of the side-branch in (iii) and
  • and the main-branch in (iv).

A delta wing-shaped cell design belonging to the class of slotted-tube stents was used for all simulations.
The length (LS) and diameter (DS) were

  • fixed at 9|10-2 m and 3|10-2 m, respectively, for the MB stent.

All stents were assumed to be perfectly apposed to the lumen of MB and the intrinsic strut shape was modeled as

  • square with length 10-4 m.

The continuity and momentum equations were solved within the arterial lumen, where

vf , rho~1060 kg=m3, P and m are

  • velocity
  • density
  • pressure and the
  • viscosity of blood.

In order to capture boundary layer effects at the lumen-wall (or mural) surface, a Carreau model was employed for

  • all the simulations to account for shear thinning behavior of blood at low shear rates

In the arterial lumen, drug transport followed advection-diffusion process.  Similar to the momentum transport in the arterial lumen, the continuity equation was solved within the arterial wall by assuming it as a porous medium.

A finite volume solver (Fluent, ANSYS Inc.) was utilized to perform the coupled flow and drug transport simulations. The semi-implicit method for pressure-linked equations-consistent (SIMPLEC) algorithm was used with second order spatial accuracy. A second order discretization scheme was used to solve the pressure equation and second order  upwind schemes were used for the momentum and concentration variables.

Simulations for each case were performed

  • for at least 2500 iterations or
  • until there was a 1028 reduction in the mass transport residual.

Drug distribution in non-bifurcating vessels

Constant flow simulations generate local recirculation zones juxtaposed to the stent which in turn act as

  • secondary sources of drug deposition and
  • induce an asymmetric tissue drug distribution profile in the longitudinal flow direction.

Our3D computational model predicts a far more extensive fluid mechanic effect on drug deposition than previously appreciated in two-dimensional (2D) domains.

Within the stented region, drug deposition on the mural interface quantified as

  • the area-weighted average drug concentration (AWAC)
  • in the distal segment of the stent is 12% higher than the proximal segment

Total drug uptake in the arterial wall denote as volume-weighted average concentration (VWAC) is highest in the middle segment of the stent and 5% higher than the proximal stent region

Increased mural drug deposition along the flow direction in a non-bifurcating arterial vessel.

Inset shows a high magnification image of drug pattern in the distal stent segment outlined by black dashed line.
The entire stent is divided into three equal sections denoted as proximal, middle and distal sections, respectively
and the same notation is followed for subsequent analyses.


These observations indicate that the flow-mediated effect induced by the presence of the stent in the artery

  • is maximal on the mural surface and
  • increases in the longitudinal flow direction.

Further, these results suggest that transmural diffusion-mediated transport sequesters drug from both

  • the proximal and distal portions of the stent
  • into the central segment of the arterial wall beneath the stent.

Predicted levels of average drug concentration varied exponentially

  • with linear increments of inlet flow rate

but maintained similar relationship between the inter-segment concentration levels within the stented region.

Stent position influences drug distribution in bifurcated beds

The location of the stent directly modulates

  • the extent to which drug is deposited on the arterial wall as well as
  • spatial gradients that are established in arterial drug distribution.

Similar to the non-bifurcating vessel case,

  • peaks in drug deposition occur directly beneath the stent struts regardless of the relative location of the SB with respect to the stent. However,
  • drug distribution and corresponding spatial heterogeneity within inter-strut regions depend on the stent location with respect to the flow divider.
  • Mural drug deposition is a function of relative stent position with respect to the side-branch and Reynolds number in arterial bifurcations.

Impact of flow on drug distribution in bifurcations

One can appreciate how blood flow and flow dividers affect arterial drug deposition, and especially on inter-strut drug deposition.

  • Drug deposition within the stented-region of MB  and the entire SB significantly decreases with flow acceleration regardless of stent placement.

Simulations predicted

Local endovascular drug delivery was long assumed to be governed by diffusion alone. The impact of flow was
thought to be restricted to systemic dilution.

  • 2D computational models suggested a complex interplay between the stent and blood flow
  1. Arterial drug deposition is a function of stent location.   http://dx.doi.org/10.1371/journal.pone.0008105.g005
  2. Arterial drug deposition is mediated by flow in bifurcated beds.
  • extensive flow-mediated drug delivery in bifurcated vascular beds where the drug distribution patterns are heterogeneous and sensitive to relative stent position and luminal flow.

A single DES in the MB coupled with large retrograde luminal flow on the lateral wall of the side-branch (SB) can provide drug deposition on the SB lumen-wall interface, except

  • when the MB stent is downstream of the SB flow divider.
  • the presence of the SB affects drug distribution in the stented MB.

Fluid mechanic effects play an even greater role than in the SB

  • especially when the DES is across and downstream to the flow divider
  • and in a manner dependent upon

    the Reynolds number.


We presented the hemodynamic effects on drug distribution patterns using a

  • simplified uniform-cell stent design, though our methodology is adaptable to
    several types of stents with variable design features.

Variability in arterial drug distribution due to other geometric and morphologic aspects such as

  • bifurcation angle, arterial taper as well as presence of a trifurcation can also be understood using our computational framework.

Further, performance of a candidate DES using other commonly used stenting procedures for bifurcation lesions such as culotte and crush techniques can be quantified based on their resulting drug distribution patterns.

Other Related Articles that were published on this Open Access Online Scientific Journal include the following:

Vascular Repair: Stents and Biologically Active Implants

Larry H Bernstein, MD, FACP and Aviva Lev-Ari, RN, PhD, 5/4/2013

Modeling Targeted Therapy

Larry H Bernstein, MD, FACP 3/2/2013

Quantum Biology And Computational Medicine

Larry H Bernstein, MD, FACP 4/3/2013

Virtual Biopsy – is it possible?

Larry H Bernstein, MD, FACP 3/3/2013

Reprogramming cell fate  3/2/2013

Larry H Bernstein, MD, FACP

How Methionine Imbalance with Sulfur-Insufficiency Leads to Hyperhomocysteinemia

Larry H Bernstein, MD, FACP 4/4/2013

Amyloidosis with Cardiomyopathy

Larry H Bernstein, MD, FACP 3/31/2013

Nitric Oxide, Platelets, Endothelium and Hemostasis

Larry H Bernstein, MD, FACP 11/8/2012

Mitochondrial Damage and Repair under Oxidative Stress

Larry H Bernstein, MD, FACP 10/28/2012

Endothelial Function and Cardiovascular Disease

Larry H Bernstein, MD, FACP 10/25/2012

Endothelial Dysfunction, Diminished Availability of cEPCs, Increasing CVD Risk for Macrovascular Disease –Therapeutic Potential of cEPCs

Aviva Lev-Ari, PhD, RN 8/27/2012

Prostacyclin and Nitric Oxide: Adventures in Vascular Biology – A Tale of Two Mediators

Aviva Lev-Ari, RN, PhD, 4/30/2013

Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis

Aviva Lev-Ari, PhD, 4/28/2013


Revascularization: PCI, Prior History of PCI vs CABG

Aviva Lev-Ari, PhD, 4/25/2013


Revascularization: PCI, Prior History of PCI vs CABG

Aviva Lev-Ari, PhD, RN 4/25/2013


Cholesteryl Ester Transfer Protein (CETP) Inhibitor: Potential of Anacetrapib to treat Atherosclerosis and CAD

Aviva Lev-Ari, PhD, RN 4/7/2013


Hypertriglyceridemia concurrent Hyperlipidemia: Vertical Density Gradient Ultracentrifugation a Better Test to Prevent Undertreatment of High-Risk Cardiac Patients

Aviva Lev-Ari, PhD, RN 4/4/2013


Fight against Atherosclerotic Cardiovascular Disease: A Biologics not a Small Molecule – Recombinant Human lecithin-cholesterol acyltransferase (rhLCAT) attracted AstraZeneca to acquire AlphaCore

Aviva Lev-Ari, PhD, RN 4/3/2013


High-Density Lipoprotein (HDL): An Independent Predictor of Endothelial Function & Atherosclerosis, A Modulator, An Agonist, A Biomarker for Cardiovascular Risk

Aviva Lev-Ari, PhD, RN 3/31/2013


Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI

Aviva Lev-Ari, PhD, RN 3/10/2013


Genomics & Genetics of Cardiovascular Disease Diagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013

Lev-Ari, A. and L H Bernstein 3/7/2013


The Heart: Vasculature Protection – A Concept-based Pharmacological Therapy including THYMOSIN

Aviva Lev-Ari, PhD, RN 2/28/2013


Arteriogenesis and Cardiac Repair: Two Biomaterials – Injectable Thymosin beta4 and Myocardial Matrix Hydrogel

Aviva Lev-Ari, PhD, RN 2/27/2013


Coronary artery disease in symptomatic patients referred for coronary angiography: Predicted by Serum Protein Profiles

Aviva Lev-Ari, PhD, RN 12/29/2012


Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment

Bernstein, HL and Lev-Ari, A. 11/28/2012


Peroxisome proliferator-activated receptor (PPAR-gamma) Receptors Activation: PPARγ transrepression for Angiogenesis in Cardiovascular Disease and PPARγ transactivation for Treatment of Diabetes

Aviva Lev-Ari, PhD, RN 11/13/2012


Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination?

Aviva Lev-Ari, PhD, RN 10/19/2012


Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation

Aviva Lev-Ari, PhD, RN 10/4/2012


Inhibition of ET-1, ETA and ETA-ETB, Induction of NO production, stimulation of eNOS and Treatment Regime with PPAR-gamma agonists (TZD): cEPCs Endogenous Augmentation for Cardiovascular Risk Reduction – A Bibliography

Aviva Lev-Ari, PhD, RN 10/4/2012


Positioning a Therapeutic Concept for Endogenous Augmentation of cEPCs — Therapeutic Indications for Macrovascular Disease: Coronary, Cerebrovascular and Peripheral

Aviva Lev-Ari, PhD, RN 8/29/2012


Cardiovascular Outcomes: Function of circulating Endothelial Progenitor Cells (cEPCs): Exploring Pharmaco-therapy targeted at Endogenous Augmentation of cEPCs

Aviva Lev-Ari, PhD, RN 8/28/2012


Endothelial Dysfunction, Diminished Availability of cEPCs, Increasing CVD Risk for Macrovascular Disease – Therapeutic Potential of cEPCs

Aviva Lev-Ari, PhD, R N 8/27/2012


Vascular Medicine and Biology: CLASSIFICATION OF FAST ACTING THERAPY FOR PATIENTS AT HIGH RISK FOR MACROVASCULAR EVENTS Macrovascular Disease – Therapeutic Potential of cEPCs

Aviva Lev-Ari, PhD, RN 8/24/2012


Cardiovascular Disease (CVD) and the Role of agent alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production

Aviva Lev-Ari, PhD, RN 7/19/2012


Resident-cell-based Therapy in Human Ischaemic Heart Disease: Evolution in the PROMISE of Thymosin beta4 for Cardiac Repair

Aviva Lev-Ari, PhD, RN 4/30/2012


Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes

Aviva Lev-Ari, PhD, RN 5/29/2012


Macrovascular Disease – Therapeutic Potential of cEPCs: Reduction Methods for CV Risk

Aviva Lev-Ari, PhD, RN 7/2/2012


Mitochondria Dysfunction and Cardiovascular Disease – Mitochondria: More than just the “powerhouse of the cell”

Aviva Lev-Ari, PhD, RN 7/9/2012


Bystolic’s generic Nebivolol – positive effect on circulating Endothelial Proginetor Cells endogenous augmentation

Aviva Lev-Ari, PhD, RN 7/16/2012


Arteriogenesis and Cardiac Repair: Two Biomaterials – Injectable Thymosin beta4 and Myocardial Matrix Hydrogel

Aviva Lev-Ari, PhD, RN 2/27/2013


Cardiac Surgery Theatre in China vs. in the US: Cardiac Repair Procedures, Medical Devices in Use, Technology in Hospitals, Surgeons’ Training and Cardiac Disease Severity”

Aviva Lev-Ari, PhD, RN 1/8/2013


Heart Remodeling by Design – Implantable Synchronized Cardiac Assist Device: Abiomed’s Symphony

Aviva Lev-Ari, PhD, RN 7/23/2012


Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI

Aviva Lev-Ari, PhD, RN 3/10/2013


Dilated Cardiomyopathy: Decisions on implantable cardioverter-defibrillators (ICDs) using left ventricular ejection fraction (LVEF) and Midwall Fibrosis: Decisions on Replacement using late gadolinium enhancement cardiovascular MR (LGE-CMR)

Aviva Lev-Ari, PhD, RN 3/10/2013

The Heart: Vasculature Protection – A Concept-based Pharmacological Therapy including THYMOSIN

Aviva Lev-Ari, PhD, RN 2/28/2013

FDA Pending 510(k) for The Latest Cardiovascular Imaging Technology

Aviva Lev-Ari, PhD, RN 1/28/2013

PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity

Aviva Lev-Ari, PhD, RN 1/10/2013

The ACUITY-PCI score: Will it Replace Four Established Risk Scores — TIMI, GRACE, SYNTAX, and Clinical SYNTAX

Aviva Lev-Ari, PhD, RN 1/3/2013

Coronary artery disease in symptomatic patients referred for coronary angiography: Predicted by Serum Protein Profiles

Aviva Lev-Ari, PhD, RN 12/29/2012

Heart Renewal by pre-existing Cardiomyocytes: Source of New Heart Cell Growth Discovered

Aviva Lev-Ari, PhD, RN 12/23/2012

Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic Stroke – Atherosclerosis.

Aviva Lev-Ari, PhD, RN 10/30/2012

To Stent or Not? A Critical Decision

Aviva Lev-Ari, PhD, RN 10/23/2012

New Definition of MI Unveiled, Fractional Flow Reserve (FFR)CT for Tagging Ischemia

Aviva Lev-Ari, PhD, RN 8/27/2012

Ethical Considerations in Studying Drug Safety — The Institute of Medicine Report

Aviva Lev-Ari, PhD, RN 8/23/2012

New Drug-Eluting Stent Works Well in STEMI

Aviva Lev-Ari, PhD, RN 8/22/2012

Expected New Trends in Cardiology and Cardiovascular Medical Devices

Aviva Lev-Ari, PhD, RN 8/17/2012

Coronary Artery Disease – Medical Devices Solutions: From First-In-Man Stent Implantation, via Medical Ethical Dilemmas to Drug Eluting Stents

Aviva Lev-Ari, PhD, RN 8/13/2012


Percutaneous Endocardial Ablation of Scar-Related Ventricular Tachycardia

Aviva Lev-Ari, PhD, RN 7/18/2012


Competition 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)

Aviva Lev-Ari, PhD, RN 6/22/2012


Global 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

Aviva Lev-Ari, PhD, RN 6/22/2012


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Modeling Targeted Therapy

Reporter: Larry H. Bernstein, MD, FCAP

Some Perspectives on Network Modeling in Therapeutic Target Prediction
R Albert, B DasGupta and N Mobasheri
Biomedical Engineering and Computational Biology Insights 2013; 5: 17–24    http://dx.doi.org/BECBI/Albert_DasGupta_ Mobasheri
Key steps of a typical therapeutic target identification problem include synthesizing or inferring the complex network of interactions relevant to the disease, connecting this network to the disease-specific behavior, and predicting which components are key mediators of the behavior

Journal of Computational Biology

Journal of Computational Biology (Photo credit: Wikipedia)

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A revolutionary microchip-based human disease model for testing drugs

Reporter: Ritu Saxena, Ph.D.

Researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, have developed lung-on-a-microfluid chip and shown that it mimic human lung function in response to Interluekin-2 (IL-2) and mechanical strain. Authors describe it as “a “lung-on-a-chip” that reconstituted the alveolar-capillary interface of the human lung and exposed it to physiological mechanical deformation and flow; in other words, it breathed rhythmically much like a living lung”.

The model was developed by Hu et al and reported earlier in the journal Science in 2010. The group has now been successful in demonstrating that lung-on-a-chip can act as a drug-testing model for pulmonary edema. Infact, Hu et al were able to predict the activity of a new drug, GSK2193874, for edema. Authors stated “These studies also led to identification of potential new therapeutics, including angiopoietin-1 (Ang-1) and a new transient receptor potential vanilloid 4 (TRPV4) ion channel inhibitor (GSK2193874), which might prevent this life-threatening toxicity of IL-2 in the future.” The findings have been published recently in the November 7 issue of Science Translational Medicine.


To recreate lung on the microchip, the authors cultured two toes of human lung cells in parallel microchannels separated by a thin membrane. It was observed that the upper channel (alveolar) was filled with air, while the lower channel (microvascular) was filled with liquid. The observation was similar to what occurs in human lung. Breathing motion of the lung was mimicked on the chip by applying vacuum cyclically to the sides of the channels.

Mimicking pulmonary edema

Pulmonary edema is a condition characterized by the abnormal buildup of fluid in the air sacs of the lungs, which leads to shortness of breath. It is often caused when the heart is not able to pump blood to the body efficiently, it can back up into the veins that take blood through the lungs to the left side of the heart. As the pressure in these blood vessels increases, fluid is pushed into the air spaces (alveoli) in the lungs. This fluid reduces normal oxygen movement through the lungs. This and the increased pressure can lead to shortness of breath.

Hu and colleagues observed that when IL-2 was added to the microvascular channel, the fluid started to leak into the alveolar compartment of the chip. This process is a reproduction of what happens in edema. Further, adding cyclic mechanical strain along with IL-2 compromised the pulmonary barrier even further and leading to a threefold increase in leakage.

Drug-testing model

Once the authors established the pulmonary disease model on the microchip, they tested against a novel pharmacological agent, GSK2193874, which blocks certain ion channels activated by mechanical strain. This drug was able to inhibit leakage suggesting that it might be a viable treatment option for patients with pulmonary edema who are being mechanically ventilated. A major advantage of using this model is avoiding the use of animal models for research.

Future perspective

The lung-on-a-chip model developed by Hu et al could be used to test novel agents for pulmonary edema.

Editorial note on the article in Science translational medicine article states “The next step is to hook this lung up to other chip-based organs− heart, liver, pancreas, etc.−with the goal of one day being able to rapidly screen many drugs and conditions that could affect patient health.”


Journal articles

Hul D, et al. A Human Disease Model of Drug Toxicity−Induced Pulmonary Edema in aLung-on-a-Chip. Microdevice Sci Transl Med. 2012 Nov 7;4(159):159ra147.http://www.ncbi.nlm.nih.gov/pubmed/23136042

Hul D et al Reconstituting organ-level lung functions on a chipScience. 2010 Jun 25;328(5986):1662-8. http://www.ncbi.nlm.nih.gov/pubmed/20576885

News brief

Video link to lung-on-a-chip http://wyss.harvard.edu/viewpage/240/

Sciencedaily report, November 7, 2012 http://www.sciencedaily.com/releases/2012/11/121107141044.htm

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Atrial Fibrillation: The Latest Management Strategies

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 8/5/2013

Ischemic strokes are the most common type of AFib-related stroke5 and can be extremely debilitating.6,7 It’s important to help your patients understand the risk of ischemic stroke and how you can help lower that risk.

Nearly 9 out of 10 AFib-related strokes are ischemic, and most are cardioembolic5,8,9

  • Cardioembolic strokes are most commonly caused by AFib9,10
  • Hemorrhagic strokes account for approximately 10% of AFib-related strokes5
  • AFib-related ischemic strokes are primarily caused by an embolus formed in the left atrial appendage of the heart11

Ischemic strokes can be devastating, often resulting in irreversible brain damage2

  • Debilitating effects of a stroke include paralysis, slurred speech, and memory loss12
    • Every second, ≈32,000 brain cells can die due to hypoxia from lack of blood flow4
    • In 1 minute, nearly 2 million brain cells can die—increasing the risk of disability or death2-4
  • Severely disabling stroke is frequently rated by patients as equivalent to or worse than death13

Strokes are a leading cause of disability in the US14

The good news is you can significantly reduce your AFib patients’ risk of ischemic stroke with anticoagulation therapy.11,15,16 By keeping them appropriately anticoagulated, you can help your patients avoid the devastation of ischemic stroke.11

AFib=atrial fibrillation.


  1. Types of stroke. Johns Hopkins Medicine Web site. http://www.hopkinsmedicine.org/healthlibrary/printv.aspx?d=85,P00813. Accessed August 9, 2012.
  2. Maas MB, Safdieh JE. Ischemic stroke: pathophysiology and principles of localization. Hospital Physician Neurology Board Review Manual. 2009;13:1-16.http://www.turner-white.com/pdf/brm_Neur_V13P1.pdf. Accessed February 1, 2013.
  3. Rosamond WD, Folsom AR, Chambless LE, et al. Stroke incidence and survival among middle-aged adults: 9-year follow-up of the Atherosclerosis Risk in Communities (ARIC) cohort. Stroke. 1999;30:736-743.
  4. Saver JL. Time is brain—quantified. Stroke. 2006;37:263-266.
  5. Mercaldi CJ, Ciarametaro M, Hahn B, et al. Cost efficiency of anticoagulation with warfarin to prevent stroke in Medicare beneficiaries with nonvalvular atrial fibrillation. Stroke. 2011;42:112-118.
  6. Vemmos KN, Tsivgoulis G, Spengos K, et al. Anticoagulation influences long-term outcome in patients with nonvalvular atrial fibrillation and severe ischemic stroke. Am J Geriatr Pharmacother. 2004;2:265-273.
  7. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke. 1996;27:1760-1764.
  8. Grau AJ, Weimar C, Buggle F, et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German Stroke Data Bank. Stroke. 2001;32:2559-2566.
  9. Bogousslavsky J, Van Melle G, Regli F, Kappenberger L. Pathogenesis of anterior circulation stroke in patients with nonvalvular atrial fibrillation: the Lausanne Stroke Registry. Neurology. 1990;40:1046-1050.
  10. Freeman WD, Aguilar MI. Prevention of cardioembolic stroke. Neurotherapeutics. 2011;8:488-502.
  11. Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm SocietyCirculation. 2006;114:700-752.
  12. Effects of stroke. American Stroke Association Web site. http://www.strokeassociation.org/STROKEORG/AboutStroke/EffectsofStroke/Effects-of-Stroke_UCM_308534_SubHomePage.jsp. Accessed December 8, 2012.
  13. Gage BF, Cardinalli AB, Owens DK. The effect of stroke and stroke prophylaxis with aspirin or warfarin on quality of life. Arch Intern Med. 1996;156:1829-1836.
  14. Centers for Disease Control and Prevention (CDC). Prevalence of Stroke—United States, 2006-2010. MMWR Morb Mortal Wkly Rep. 2012;61:379-382.
  15. Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med. 2009;151:297-305.
  16. Lip GYH, Andreotti F, Fauchier L, et al. Bleeding risk assessment and management in atrial fibrillation patients: a position document from the European Heart Rhythm Association, endorsed by the European Society of Cardiology Working Group on Thrombosis. Europace. 2011;13:723-746.



Straightforward, informed answers to your most important questions about living

with atrial fibrillation – the most common sustained cardiac arrhythmia.

Written by

Hugh G. Calkins, M.D., Director of the Arrhythmia Service

and Electrophysiology Lab at The Johns Hopkins Hospital,

and Ronald Berger, M.D.,

If you’ve ever run up a flight of stairs, chased a tennis ball across the court, or reacted in fright at a scary movie, you know what a pounding heart feels like…

But for the 2.3 million Americans who suffer from atrial fibrillation (AF or AFib), a racing heart is a way of life. Simple tasks like getting out of bed in the morning or rising from a chair can cause dizziness, weakness, shortness of breath, or heart palpitations. For these people, AF severely impairs quality of life – and even when symptoms stemming from AF are mild, the disorder can seriously impact health, increasing the risk of stroke and heart failure.

AF can be a debilitating even deadly condition. Fortunately, it can be successfully managed – but there are various approaches for treating AF or preventing a recurrence. How do you and your doctor choose which approach is right for you?

If you or a loved one has AF, there are so many questions: Do I need an anticoagulant… should I be taking medication to control my heart rate… will my symptoms respond to cardioversion… if I need an antiarrhythmic drug to control AF episodes, which one should I take… when is an ablation procedure appropriate… and more.

It’s critically important to learn everything you can now — so you can partner with your doctor effectively, ask the right questions, and understand the answers.

To help you, we asked two eminent experts at Johns Hopkins to share their expertise and hands-on experience with arrhythmia patients in an important new report, Atrial Fibrillation: The Latest Management Strategies.

Dr. Hugh Calkins and Dr. Ronald Berger are ideally positioned to help you understand and manage your AF. Together with their colleagues at Johns Hopkins, they perform approximately 2,000 electrophysiology procedures and 200 pulmonary vein isolation procedures for atrial fibrillation each year.

Hugh Calkins, M.D. is the Nicholas J. Fortuin, M.D. Professor of Cardiology, Professor of Pediatrics, and Director of the Arrhythmia Service, the Electrophysiology Lab, and the Tilt Table Diagnostic Lab at The Johns Hopkins Hospital. He has clinical and research interests in the treatment of cardiac arrhythmias with catheter ablation, the role of device therapy for treating ventricular arrhythmias, the evaluation and management of syncope, and the study of arrhythmogenic right ventricular dysplasia.

Ronald Berger, M.D., Ph.D., a Professor of Medicine and Biomedical Engineering at Johns Hopkins, is Director of the Electrophysiology Fellowship Program at The Johns Hopkins Hospital. He serves on the editorial board for two major journals in the cardiovascular field and has written and coauthored more than 100 articles and book chapters.

Atrial Fibrillation: The Latest Management Strategies is now available to you in a digital PDF download and print version.

“I feel like my heart is going to jump out of my chest…” 

An arrhythmia is an abnormality in the timing or pattern of the heartbeat, causing the heart to beat too rapidly, too slowly, or irregularly. Sounds pretty straightforward, but there’s a lot we don’t know about why the heart rhythm goes awry… or the best way to treat it.

In Atrial Fibrillation: The Latest Management Strategies, we focus on what we DO know. In page after page of this comprehensive report, we address your most serious concerns about living with AF, such as:

  • I don’t have any symptoms. Is my problem definitely AF?
  • Can drinking alcohol trigger or worsen AF?
  • Is every person who has AF at risk for a stroke?
  • If my doctor suspects AF, will I have to wear an implantable or event monitor to be sure?
  • Why does AF often show up later in life?
  • What would you recommend to the older patient – 75 and older – who has AF but no bothersome symptoms?
  • What do you recommend for the person with longstanding persistent AF?
  • Is the AF experienced by an otherwise healthy person different from that of a person with underlying heart disease or other health issues?
  • What are the differences among: paroxysmal AF, persistent AF, and longstanding persistent AF?
  • What is the “pill-in-the-pocket” approach to AF?

Anticoagulation Therapy: What You Should Know

While AF is generally not life threatening, for some patients it can increase the likelihood of blood clots forming in the heart. And if a clot travels to the brain, a stroke will result. Anticoagulation therapy is used to prevent blood clot formation in people with AF…

  • Why is anticoagulation therapy with warfarin (Coumadin) needed for some people with AF?
  • How is the use of warfarin monitored?
  • How does a doctor determine if a patient with AF needs to take warfarin?
  • What’s the CHADS2 score and how is it used?
  • If a patient’s CHADS2 score is 1, how do you decide between aspirin and warfarin, or nothing at all?
  • Why is it so difficult to keep within therapeutic range with warfarin?
  • Can I test my INR (a test measuring how long it takes blood to clot) at home?
  • What happens if my INR is too high?
  • What options are available if a patient cannot take warfarin?
  • What are the benefits of dabigatran, a new blood-thinning alternative to warfarin therapy?

Symptom Control: The Art of Rate and Rhythm Control

For many patients and their doctors, it’s difficult to achieve and maintain heart rhythm. Two key management strategies are used: heart rate and heart rhythm control. In Atrial Fibrillation: The Latest Management Strategies, you’ll read an in-depth discussion of the benefits of rate versus rhythm control for AF:

  • What have we learned from the AFFIRM study, and how has this knowledge affected the management of AF?
  • What is catheter ablation of the AV (atrioventricular) node?
  • Why is cardioversion needed?
  • Are there different types of cardioversion?
  • What is chemical cardioversion? What is electrical cardioversion?
  • Can medication be used to convert the heart back to normal sinus rhythm?
  • Which antiarrhythimic drugs are used to treat AF?
  • How is catheter ablation for AF performed?
  • What is pulmonary vein antrum isolation (PVAI) and how is it performed?
  • Who are the best candidates for PVAI?

There’s more to Atrial Fibrillation: The Latest Management Strategies, much more.

We explain surgical ablation of AF, a procedure performed through small incisions in the chest wall… discuss when it’s appropriate to seek a second opinion… take a close look at strokes and explain the warning signs and differences among ischemic, thrombotic, embolic, and hemorrhagic strokes… and provide an arrhythmia glossary of key AF terms used by electrophysiologists and cardiologists.

Direct to You From Johns Hopkins

Atrial Fibrillation: The Latest Management Strategies is designed to give you unprecedented access to the expertise of the hospital ranked #1 of America’s Best Hospitals for 21 consecutive years 1991-2011 by U.S. News & World Report. You simply won’t find a more knowledgeable and trustworthy source of the medical information you require. A tradition of discovery and medical innovation is the hallmark of Johns Hopkins research. Since its founding in 1889, The Johns Hopkins Hospital has led the way transferring the discoveries made in the laboratory to the administration of effective patient care. No one institution has done more to earn the trust of the men and women diagnosed with AF and other cardiovascular conditions.

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Reporter: Aviva Lev-Ari, PhD, RN

New Life – The Healing Promise of Stem Cells






Diseases and conditions where stem cell treatment is promising or emerging. Source: Wikipedia
Since the late 1990s, the Technion has been at the forefront of stem-cell research. Stem cells are the master keys because they can be converted into many different kinds of cells, opening many different doors to potential cures and treatments. Beating heart tissue is one of the major stem cell achievements from the Technion.
Healing the Heart
Technion scientists showed this year that they can turn skin tissue from heart attack patients into fresh, beating heart cells in a first step towards a new therapy for the condition. The procedure may eventually help scores of people who survive heart attacks but are severely debilitated by damage to the organ.
By creating new heart cells from a patient’s own tissues, doctors avoid the risk of the cells being rejected by the immune system once they are transplanted.Though the cells were not considered safe enough to put back into patients, they appeared healthy in the laboratory and beat in time with other cells in animal models.
“We have shown that it’s possible to take skin cells from an elderly patient with advanced heart failure and end up with his own beating cells in a laboratory dish that are healthy and young – the equivalent to the stage his heart cells were in when he was just born,” Prof. Lior Gepstein told the British national paper The Guardian.

Pancreatic Tissue for Diabetes

Prof. Shulamit Levenberg of the Technion, who has spent many years trying to create replacement human organs by building them up on a “scaffold,” has created tissue from the insulin-producing islets of Langerhans in the pancreas surrounded by a three-dimensional network of blood vessels.The tissue she and her team created has significant advantages over traditional transplant material that has been harvested from healthy pancreatic tissue.

“We have shown that the three-dimensional environment and the engineered blood vessels support the islets – and this support is important for the survival of the islets and for their insulin secretion activity”, says Prof. Levenberg of the Department of Biomedical Engineering.

In the Bones

BonusBio - Health News - Israel

In collaboration with industry and global research partners, Technion scientists have grown human bone from stem cells in a laboratory. The development opens the way for patients to have broken bones repaired or even replaced with entire new ones grown outside the body from a patient’s own cells. The researchers started with stem cells taken from fat tissue. It took around a month to grow them into sections of fully-formed living human bone up to a couple of inches long. The success was reported by the UK national paper The Telegraph.

Stem Cell Proliferation

““These are our next generation of scientists and Nobel Laureates,” says Prof. Dror Seliktar, of the Department of Biomedical Engineering. “The future of the Technion relies on that.”

Seliktar and his research team at the Lokey Center for Biomaterials and Tissue Regeneration at Technion is working on a new material for the mass production of stem cells to make their commercial use viable on an industrial scale.

“In the biotechnology industries, there is an inherent need for expanding populations of stem cells for therapeutic purposes,” says Seliktar, who has published over 50 papers in the field, won over 14 awards and launched one of Israel’s promising biotech startups, Regentis Biomaterials.

Read more.

Prof. Joseph Itskovitz-Eldor of the Faculty of Medicine was on the international team that in 1998 first discovered the potential of stem cells to form any kind of tissue and pioneered stem-cell technology. The breakthrough garnered headlines around the world. He is the Director of the Technion Stem Cell Center.


Other posts on this Scientific Web Site about innovations completed on this topic at the Technion are cited below:

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