Feeds:
Posts
Comments

Posts Tagged ‘American Heart Association’

Prediction of Occurrence of Cardiovascular Events Independently of Left Ventricular Mass in Hypertensive Patients: Monitoring of Timing of Korotkoff Sounds as Indicator of Arterial Stiffness

Posted in Atherogenic Processes & Pathology, Frontiers in Cardiology and Cardiovascular Disorders, HTN, Origins of Cardiovascular Disease, tagged , , , , , on May 20, 2013| 1 Comment »

Reporter: Aviva Lev-Ari, PhD, RN
  • Original Article

HYPERTENSIONAHA.113.01039 Published online before print May 20, 2013,doi: 10.1161/​HYPERTENSIONAHA.113.01039

Arterial Stiffness From Monitoring of Timing of Korotkoff Sounds Predicts the Occurrence of Cardiovascular Events Independently of Left Ventricular Mass in Hypertensive Patients

  1. Philippe Gosse,
  2. Antoine Cremer,
  3. Georgios Papaioannou,
  4. Sunthareth Yeim

+Author Affiliations


  1. From the Department of Cardiology and Hypertension, University Hospital of Bordeaux, Bordeaux, France.
  1. Correspondence to Philippe Gosse, Department of Cardiology and Hypertension, University Hospital of Bordeaux, Hopital Saint Andre, 1 Rue Jean Burguet, 33075 Bordeaux, France. E-mail philippe.gosse@chu-bordeaux.fr

Abstract

Several studies have established that the increase in arterial stiffness (AS) is a cardiovascular risk factor but to date no studies have evaluated in hypertensive patients its prognostic value in comparison with another powerful risk factor, left ventricular mass (LVM) as measured by echocardiography. We prospectively evaluated the prognostic value of AS and LVM in patients with essential hypertension. The population studied comprised 793 patients (56% men) aged 54±14 years. For 519 patients, baseline measurements were made before any antihypertensive treatment, for 274 patients, the measurement were obtained during the follow-up period under antihypertensive treatment. AS was assessed from ambulatory monitoring of blood pressure and timing of Korottkoff sounds. Left ventricular mass was measured in 523 patients. After a mean follow-up of 97 months, 122 cardiovascular events were recorded in the whole population and 74 in the group with LVM determination. AS as continuous or discontinuous variable was independently related to cardiovascular events. The existence or not of antihypertensive treatment at the time of its measurement did not affect its prognostic value. When LVM was forced in the model, AS remained significantly related to cardiovascular events. Thus, AS has an independent prognostic value in the hypertensive, whether measured before or after the administration of antihypertensive treatment. This prognostic value persists after taking LVM into account.

Key Words:

  • Received January 10, 2013.
  • Revision received March 25, 2013.
  • Accepted April 22, 2013.

http://hyper.ahajournals.org/content/early/2013/05/20/HYPERTENSIONAHA.113.01039.abstract.html?papetoc

Read Full Post »

Treatment, Prevention and Cost of Cardiovascular Disease: Current & Predicted Cost of Care and the Potential for Improved Individualized Care Using Clinical Decision Support Systems

Posted in Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Computational Biology/Systems and Bioinformatics, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, HealthCare IT, HTN, International Global Work in Pharmaceutical, Medical and Population Genetics, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Molecular Genetics & Pharmaceutical, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacogenomics, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, Technology Transfer: Biotech and Pharmaceutical, Uncategorized, tagged , , , , on May 15, 2013| 11 Comments »

Treatment, Prevention and Cost of Cardiovascular Disease: Current & Predicted Cost of Care and the Potential for Improved Individualized Care Using Clinical Decision Support Systems

Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC

Author and Curator: Larry H Bernstein, MD, FACP

and

Curator: Aviva Lev-Ari, PhD, RN

This article has the following FIVE parts:

1. Forecasting the Impact of Heart Failure in the United States : A Policy Statement From the American Heart Association

2. A Case Study from the GENETIC CONNECTIONS — In The Family: Heart Disease Seeking Clues to Heart Disease in DNA of an Unlucky Family

3. Arterial Stiffness and Cardiovascular Events : The Framingham Heart Study

4. Arterial Elasticity in Quest for a Drug Stabilizer: Isolated Systolic Hypertension
caused by Arterial Stiffening Ineffectively Treated by Vasodilatation Antihypertensives

5. Clinical Decision Support Systems: Realtime Clinical Expert Support — Biomarkers of Cardiovascular Disease : Molecular Basis and Practical Considerations

 

1. Forecasting the Impact of Heart Failure in the United States : A Policy Statement From the American Heart Association

PA Heidenreich, NM Albert, LA Allen, DA Bluemke, J Butler, et al. Circulation: Heart Failure 2013;6.
Print ISSN: 1941-3289, Online ISSN: 1941-3297.

Heart failure (HF) poses a major burden on productivity and cost of national healthcare expenditures

  • among older Americans, more are hospitalized for HF than for any other medical condition.

As the population ages, the prevalence of HF is expected to increase.

The purpose of this report is to

  • provide an in-depth look at how the changing demographics in the United States will impact the prevalence and cost of care for HF for different US populations.

 Projections of HF Prevalence

Prevalence estimates for HF were determined from

 Projections of the US Population With HF From 2010 to 2030 for Different Age Groups

Year

All ages

18-44 y

45-64 y

65-79 y

> 80
2012 5 813 262 396 578 1 907 141 2 192 233 1 317 310
2015 6 190 606 402 926 1 949 669 2 483 853 1 354 158
2020 6 859 623 417 600 1 974 585 3 004 002 1 463 436
2025 7 644 674 434 635 1 969 852 3 526 347 1 713 840
2030 8 489 428 450 275 2 000 896 3 857 729 2 180 528

Future Costs of HF

The future costs of HF were estimated by methods developed by the American Heart Association

  • project the prevalence and costs of HF from 2012 to 2030
  • factor out  the costs attributable to comorbid conditions.

The model does this by assuming that

(1) HF prevalence percentages will remain constant by age, sex, and race/ethnicity;

(2) the costs of technological innovation will rise at the current rate.

HF prevalence and costs (direct and indirect) were projected using the following steps:

1. HF prevalence and average cost per person were estimated by age group (18–44, 45–64, 65–79, ≥80 years), gender (male, female), and race/ethnicity (white non-Hispanic, white Hispanic, black, other) [32]. The initial HF cost per person and rate of increase in cost was determined for each demographic group, as a percentage of total healthcare expeditures.

2. Inflation is separately addressed by correcting dollar values from Medical Expenditure Panel Survey (MEPS) to 2010 dollars.

3. Nursing home spending triggered an adjustment. The estimates project the incremental cost of care attributable to heart failure (HF).

4. Total HF population prevalence and costs were projected by multiplying the US Census–projected population of each demographic group by the percentage prevalence and average cost

5. The total work loss and home productivity loss costs were generated by multiplying per capita work days lost attributable to HF by (1) prevalence of HF, (2) the probability of employment given HF (for work loss costs only), (3) mean per capita daily earnings, and (4) US Census population projection counts.

Projections of Indirect Costs

Indirect costs of lost productivity from morbidity and premature mortality were estimated as detailed below.
Morbidity costs represent the value of lost earnings attributable to HF and include loss of work among

  • currently employed individuals and those too sick to work, as well as
  • home productivity loss, which is the value of household services performed by household members who do not receive pay for the services.

Total Costs Attributable to Heart Failure (HF)

Projections of Total Cost of Care ($ Billions) for HF for Different Age Groups of the US Population

Year All 18–44 45–64 65–79 ≥ 80
2012
Medical 20.9 0.33 3.67 8.46 8.42
Indirect: Morbidity 5.42 0.52 1.92 2.05 0.93
Indirect: Mortality 4.35 0.66 2.53 0.98 0.18
Total 30.7 1.51 8.12 11.5 9.53
2020
Medical 31.1 0.43 4.58 14.2 11.8
Indirect: Morbidity 7.09 0.66 2.20 3.11 1.12
Indirect: Mortality 5.39 0.79 2.89 1.49 0.22
Total 43.6 1.88 9.67 18.8 13.2
2030
Medical 53.1 0.59 5.86 23.3 23.4
Indirect: Morbidity 9.80 0.91 2.54 4.48 1.87
Indirect: Mortality 6.84 0.98 3.32 2.16 0.37
Total 69.7 2.48 11.7 29.9 25.6

Excludes HF care costs that have been attributed to comorbid conditions.

Cost of Care

Total medical costs are projected to increase from $20.9 billion in 2012 to $53.1 billion in 2030, a 2.5-fold increase. Assuming continuation of current hospitalization practices, the majority (80%) of the costs stem from

  • hospitalization. Also, the majority of increase is from directs costs. Indirect costs are expected to rise as well, but at a lower rate, from $9.8 billion to $16.6 billion, an increase of 69%.

Direct costs (cost of medical care) are expected to increase at a faster rate than indirect costs because of premature deaths and lost productivity.

The total cost of HF (direct and indirect costs) is expected to increase in 2030 from the current $30.7 billion to at least $69.8 billion. This will amount to $244 for every US adult in 2030.

Thus the burden of HF for the US healthcare system will grow substantially during the next 18 years if current trends continue.

It is estimated that

  • by 2030, the prevalence of HF in the United States will increase by 25%, to 3.0%.
  • >8 million people in the US (1 in every 33) will have HF by 2030.
  • the projected total direct medical costs of HF between 2012 and 2030 (in 2010 dollars) will increase from $21 billion to $53 billion.
  • Total costs, including indirect costs for HF, are estimated to increase from $31 billion in 2012 to $70 billion in 2030.
  • If one assumes all costs of cardiac care for HF patients are attributable to HF
    (no cost attribution to comorbid conditions), the 2030 projected cost estimates of treating patients with HF will be 3-fold higher ($160 billion in direct costs).

Projections can be lowered if action is taken to reduce the health and economic burden of HF. Strategies, plans, and implementation to prevent HF and improve the efficiency of care are needed.

Causes and Stages of HF

If the projections for accelerating HF costs are to be avoided, attention to the different causes of HF and their risk factors is warranted.
HF is a clinical syndrome that results from a variety of cardiac disorders

  1. idiopathic dilated cardiomyopathy
  2. cardiac valvular disease
  3. pericarditis or pericardial effusion
  4. ischemic heart disease
  5. primary or secondary hypertension
  6. renovascular disease
  7. advanced liver disease with decreased venous return
  8. pulmonary hypertension
  9. prolonged hypoalbuminemia with generalized interstitial edema
  10. diabetic nephropathy
  11. heart muscle infiltration disease such as primary or secondary amyloidosis
  12. myocarditis
  13. rhythm disorders
  14. congenital diseases
  15. accidental trauma (war, chest trauma)
  16. toxicities (methamphetamine, cocaine, heavy metals, chemotherapy)

HF generally causes symptoms:

  • shortness of breath
  • fatigue
  • swelling (edema)
  • inability to lay flat (orthopnea, paroxysmal nocturnal dyspnea)
  • possibly cough, wheezing

In the Western world the predominant causes of HF are:

  • coronary artery disease
  • valvular disease
  • hypertension
  • viral, alcohol, methamphetamine or other drug  toxicity cardiomyopathy
  • stress (catechol toxicity, takotsubo “broken heart” cardiomyopathy)
  • atrial fibrillation/rapid heart rates
  • thyroid disease

In 2001, the American College of Cardiology and AHA practice guidelines for chronic HF promoted a classification system that encompasses 4 stages of HF.

  • Stage A: Patients at high risk for developing HF in the future but no functional or structural heart disorder.
  • Stage B: a structural heart disorder but no symptoms.
  • Stage C: previous or current symptoms of heart failure, manageable with medical treatment.
  • Stage D: advanced disease requiring hospital-based support, a heart transplant or palliative care.

Stages A and B are considered precursors to the clinical HF and are meant

  1. to alert healthcare providers to known risk factors for HF and
  2. the available therapies aimed at mitigating disease progression.

Stage A patients have risk factors for HF hypertension, atherosclerotic heart disease, and/or diabetes mellitus.

Patients with stage B are asymptomatic patients who have  developed structural heart disease from a variety of potential insults to the heart muscle such as myocardial infarction or valvular heart disease.

Stages C and D represent the symptomatic phases of HF, with stage C manageable and stage D failing medical management, resulting in marked symptoms at rest or with minimal activity despite optimal medical therapy.

Therapeutic interventions include:

  • dietary salt restriction and diuretics
  • medications known to prolong survival (beta blockers, ACE inhibitors, aldosterone inhibitors)
  • implantable devices such as pacemakers and defibrillators
  • stoppage of tobacco, toxic drugs, excess alcohol

Classic demographic risk factors for the development of HF include

  • older age, male gender, ethnicity, and low socioeconomic status.
  • comorbid disease states contribute to the development of HF
    • Ischemic heart disease
    • Hypertension

Diabetes mellitus, insulin resistance, and obesity are also linked to HF development,

  • with diabetes mellitus increasing the risk of HF by ≈2-fold in men and up to 5-fold in women.

Smoking remains the single largest preventable cause of disease and premature death in the United States.

Translation of Scientific Evidence into Clinical Practice

In multiple studies, failures to apply evidence-based management strategies are blamed for avoidable hospitalizations and/or deaths from HF

Improved implementation of guidelines can delay, mitigate or prevent the onset of HF, and improve survival. Performance improvement programs have facilitated the implementation of evidence-based therapies in both hospital and ambulatory care settings.

Care transition programs by hospitals have become more widespread

  • in an effort to reduce avoidable readmissions.

The interventions used by these programs include

  • initiating discharge planning early in the course of hospital care,
  • actively involving patients and families or caregivers in the plan of care,
  • providing new processes and systems that ensure patient understanding of the plan of care before discharge from the hospital, and
  • improving quality of care by continually monitoring adherence to national evidence-based guidelines with appropriate adaptations for individual differences in needs and responses.

In multiple studies,adherence to the HF plan of care was associated with reduced all-cause mortality as well as HF hospitalization.

It is anticipated that care transition programs may increase appropriate admissions while decreasing inappropriate admissions

This would have a potentially benenficial impact on the 30-day all-cause readmission rate that has become

  • a focus of public reporting in pay for performance.

More than a quarter of Medicare spending occurs in the last year of life, and

  • the costs of care during the last 6 months for a patient with HF have been increasing (11% from 2000 to 2007).

Improving end-of-life care cost effectiveness for patients with stage D HF will require ongoing

  • improved prediction of outcomes
  • integration of multiple aspects of care
  • educated examination of alternatives and priorities
  • improved decision-making
  • unbiased allocation of resources and coverage for this process rather than unbalanced coverage favoring catastrophic care

Palliative care, including formal hospice care, is increasingly advocated for patients with advanced HF.
Offering palliative care to patients with HF may lead to

  • more conservative (and less expensive) treatment
  • consistent with many patients’ goals for care

The use of hospice services is growing among the HF population,

  • HF now the second most common reason for entering hospice
  • but hospice declaration may impose automated restrictions on care that can impose an impediment to election of hospice

A recent study of patients in hospice care found that

  • patients with HF were more likely than patients with cancer to use hospice services longer than 6 months or to be discharged from hospice care alive.

Highlights:

1. Increasing incidence and costs of care for heart failure projected from 2012 to 2030

2. Direct costs rising at greater rate than indirect costs

3. American Heart Association has defined 4 stages of HF, the last 2 of which are advanced

4. Stages C & D are clinically overt and contribute to rehospitalization

5. Stage D accounts for a significant use of end-of-life hospice care

6. There are evidence-based guidelines for the provision of coordinated care that are not widely applied at present

Basic questions raised:

1. If stages A & B are under the radar, then what measures can best trigger the use of evidence-based guidelines for care?
2. Why are evidence-based guidelines commonly not deployed?

  • Flaws in the “evidence” due to bias, design errors, limted ability to extrapolate to the patients it should address
  • Delays in education, convincing of caretakers, and deployment
  • Inadequate resources
  • Financial or other disincentives

The arguments for introducing coordinated care and for evidence-based guidelines is strong.

Arguments AGAINST slavish imposition of evidence based medicine include genetic individuality (what is best on average is not necessarily best for each genetically and behaviorly distinct individual). Strict adherence to evidence-based guidelines also stifles innovative explorations. None-the-less, deviations from evidence-based plans should be cautious, well-documented, and well-informed, not due to mal-aligned incentives, ignorance, carelessness or error.

The question of when and how to intervene most cost effectively is unanswered. If some patients are salt-sensitive as a contribution to the prevalence of hypertension and heart failure, should EVERYONE be salt restricted or should there be a more concerted effort to define who is salt sensitive? What if it proved more cost-effective to restrict salt intake for everyone, even though many might be fine with high sodium intake, and some might even benefit from or require high sodium intake? Is it reasonable to impose costs, hurdles, even possible harm on some as a cheaper way to achieve “greater good”?
These issues are highly relevant to the proposed emphasis on holistic solutions.

2. A Case Study from the GENETIC CONNECTIONS — In The Family: Heart Disease Seeking Clues to Heart Disease in DNA of an Unlucky Family

By GINA KOLATA   2013.05.13  New York Times

Scientists are studying the genetic makeup of the Del Sontro family for

  • telltale mutations or aberrations in the DNA.

Robin Ashwood, one of Mr. Del Sontro’s sisters, found out she had extensive heart disease even though her electrocardiograms was normal. Six of her seven siblings also have heart disease, despite not having any of the traditional risk factors. Then, after a sister, just 47 years old, found out she had advanced heart disease, Mr. Del Sontro, then 43, went to a cardiologist. An X-ray of his arteries revealed the truth. Like his grand-father, his mother, his four brothers and two sisters, he had heart disease.

Now he and his extended family have joined an extraordinary federal research project that is using genetic sequencing to find factors that increase the risk of heart disease beyond the usual suspects — high cholesterol, high blood pressure, smoking and diabetes.“We don’t know yet how many pathways there are to heart disease,” said Dr. Leslie Biesecker, who directs the study Mr. Del Sontro joined. “That’s the power of genetics. To try and dissect that.”

“I had bought the dream: if you just do the right things and eat the right things, you will be O.K.,” said Mr. Del Sontro, whose cholesterol and blood pressure are reassuringly low.

3. Arterial Stiffness and Cardiovascular Events : The Framingham Heart Study

GF Mitchell, Shih-Jen Hwang, RS Vasan, MG Larson.

Circulation. 2010;121:505-511.  http://circ.ahajournals.org/content/121/4/505
http://dx.doi.org/10.1161/CIRCULATIONAHA.109.886655

Various measures of arterial stiffness and wave reflection have been proposed as cardiovascular risk markers.
Prior studies have not assessed relations of a comprehensive panel of stiffness measures to prognosis.
First-onset major cardiovascular disease events in relation to arterial stiffness

  • pulse wave velocity [PWV]
  • wave reflection
    • augmentation index
    • carotid-brachial pressure amplification)
  • central pulse pressure

were analyzed  in 2232 participants (mean age, 63 years; 58% women) in the Framingham Heart Study by a proportional hazards model. 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
  • 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; P 0.002).

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,

  • augmentation index,
  • central pulse pressure, and
  • pulse pressure amplification

were not related to cardiovascular disease outcomes in multivariable models.

Higher aortic stiffness assessed by PWV

  • is associated with increased risk for a first cardiovascular event.

Aortic PWV improves risk prediction when added to standard risk factors and may represent

  • a valuable biomarker of cardiovascular disease risk

We shall here visit a recent article by Justin D. Pearlman and Aviva Lev-Ari, PhD, RN, on

Pros and Cons of Drug Stabilizers for Arterial  Elasticity as an Alternative or Adjunct to Diuretics and Vasodilators in the Management of Hypertension, titled

4. Hypertension and Vascular Compliance: 2013 Thought Frontier – An Arterial Elasticity Focus

http://pharmaceuticalintelligence.com/2013/05/11/arterial-elasticity-in-quest-for-a-drug-stabilizer-isolated-systolic-hypertension-caused-by-arterial-stiffening-ineffectively-treated-by-vasodilatation-antihypertensives/

Speaking at the 2013 International Conference on Prehypertension and Cardiometabolic Syndrome, meeting cochair Dr Reuven Zimlichman (Tel Aviv University, Israel) argued that there is a growing number of patients for whom the conventional methods are inappropriate for

  • the definitions of hypertension
  • the risk-factor tables used to guide treatment

Most antihypertensives today work by producing vasodilation or decreasing blood volume which may be

  • ineffective treatments for patients in whom average arterial diameter and circulating volume are not the causes of hypertension and as targets of therapy may promote decompensation

In the future, he predicts, “we will have to start looking for a totally different medication that will aim to

  • improve or at least to stabilize arterial elasticity: medication that might affect factors that determine the stiffness of the arteries, like collagen, like fibroblasts.

Those are not the aim of any group of antihypertensive medications today.”

Zimlichman believes existing databases could be used to develop algorithms that focus on

  • inelasticity as a mechanism of hypertensive disease

He also points out that

  • ambulatory blood-pressure-monitoring devices can measure elasticity

http://www.theheart.org/article/1502067.do

A related article was published on the relationship between arterial stiffening and primary hypertension.

Arterial stiffening provides sufficient explanation for primary hypertension.

KH Pettersen, SM Bugenhagen, J Nauman, DA Beard, SW Omholt.

By use of empirically well-constrained computer models describing the coupled function of the baroreceptor reflex and mechanics of the circulatory system, we demonstrate quantitatively that

  • arterial stiffening seems sufficient to explain age-related emergence of hypertension.

Specifically,

  • the empirically observed chronic changes in pulse pressure with age
  • the capacity of hypertensive individuals to regulate short-term changes in blood pressure becomes impaired

The results suggest that a major target for treating chronic hypertension in the elderly  may include

  • the reestablishment of a proper baroreflex response.

http://arxiv.org/abs/1305.0727v2?goback=%2Egde_4346921_member_240018699

5. Clinical Decision Support Systems: Realtime Clinical Expert Support: Biomarkers of Cardiovascular Disease — Molecular Basis and Practical Considerations

RS Vasan.  Circulation. 2006;113:2335-2362

http://dx.doi.org/10.1161/CIRCULATIONAHA.104.482570

http://circ.ahajournals.org/content/113/19/2335

Substantial data indicate that CVD is a life course disease that begins with the evolution of risk factors that contribute to

  • subclinical atherosclerosis.

Subclinical disease culminates in overt CVD. The onset of CVD itself portends an adverse prognosis with greater

  • risks of recurrent adverse cardiovascular events, morbidity, and mortality.

Clinical assessment alone has limitations. Clinicians have used additional tools to aid clinical assessment and to enhance their ability to identify the “vulnerable” patient at risk for CVD, as suggested by a recent National Institutes of Health (NIH) panel.

Biomarkers are one such tool to better identify high-risk individuals, to diagnose disease conditions promptly for diagnosis, prognosis, and treatment guidance.

Biological marker (biomarker): A laboratory test value that is objectively measured and evaluated as an indicator of

  1. normal biological processes,
  2. pathogenic processes, or
  3. pharmacological responses to a therapeutic intervention.

Type 0 biomarker: A marker of the natural history of a disease

  • Type 0 correlates longitudinally with known clinical indices/predicts outcomes.

Type I biomarker: A marker that captures the effects of a therapeutic intervention

  • Type I assesses an aspect of treatment mechanism of action.

Type 2 biomarker (surrogate end point):  A marker intended to predict outcomes on the basis of

  • epidemiologic
  • therapeutic
  • pathophysiologic or
  • other scientific evidence.

With biomarkers monitoring disease progression or response to therapy, the patient can serve as  his or her own control (follow-up values may be compared to baseline  values).

Costs may be less important for prognostic markers when they are largely restricted to people with disease (total cost=cost per person x number to be tested, plus down-stream costs). Some biomarkers (e.g., an exercise stress test) may be used for both diagnostic and prognostic purposes.

Generally there are cost differences in establishing a prognostic value versus diagnostic value of a biomarker:

  • prognostic utility typically requires a large sample and a prospective design, whereas
  • diagnostic value often can be determined with a smaller sample in a cross-sectional design

Regardless of the intended use, it is important to remember that biomarkers that do not change disease management

  • cannot affect patient outcome and therefore
  • are unlikely to be cost-effective (judged in terms of quality-adjusted life-years gained).

Typically, for a biomarker to change management, it is important to have evidence that risk reduction strategies should vary with biomarker levels, and/or biomarker-guided management achieves advantages over a management scheme that ignores the biomarker levels.

Typically it means that biomarker levels should be modifiable by therapy.

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

  • provides empirical medical reference and
  • suggests quantitative diagnostics options.

The current design of the Electronic Medical Record (EMR) is a
linear presentation of portions of the record

  • by services
  • by diagnostic method, and
  • by date

to cite examples.

This allows perusal through a graphical user interface (GUI) that

  • partitions the information or necessary reports in a workstation entered by keying to icons.
  • presents decision support

Examples of data partitions include:

  • history
  • medications
  • laboratory reports
  • imaging
  • EKGs

The introduction of a DASHBOARD adds presentation of

  • drug reactions
  • allergies
  • primary and secondary diagnoses, and
  • critical information

about any patient the care giver needing access to the record.

A basic issue for such a tool is what information is presented and how it is displayed.

A determinant of the success of this endeavor is if it

  • facilitates workflow
  • facilitates decision-making process
  • reduces medical error.

Continuing work is in progress in extending the capabilities with model datasets, and sufficient data based on the assumption that computer extraction of data from disparate sources will, in the long run, further improve this process.

For instance, there is synergistic value in finding coincidence of:

  • ST shift on EKG
  • elevated cardiac biomarker (troponin)
  • in the absence of substantially reduced renal function.

Similarly, the conversion of hematology based data into useful clinical information requires the establishment of problem-solving constructs based on the measured data.

The most commonly ordered test used for managing patients worldwide is the hemogram that often incorporates

  • morphologic review of a peripheral smear
  • descriptive statistics

While the hemogram has undergone progressive modification of the measured features over time the subsequent expansion of the panel of tests has provided a window into the cellular changes in the

  • production
  • release
  • or suppression

of the formed elements from the blood-forming organ into the circulation. In the hemogram one can view data reflecting the characteristics of a broad spectrum of medical conditions.

Progressive modification of the measured features of the hemogram has delineated characteristics expressed as measurements of

  • size
  • density, and
  • concentration

resulting in many characteristic features of classification. In the diagnosis of hematological disorders

  • proliferation of marrow precursors
  • domination of a cell line
  • suppression of hematopoiesis

Other dimensions are created by considering

  • the maturity and size of the circulating cells.

The application of rules-based, automated problem solving should provide a valid approach to

  • the classification and interpretation of the data used to determine a knowledge-based clinical opinion.

The exponential growth of knowledge since the mapping of the human genome enabled by parallel advances in applied mathematics that have not been a part of traditional clinical problem solving.

As the complexity of statistical models has increased

  • the dependencies have become less clear to the individual.

Contemporary statistical modeling has a primary goal of finding an underlying structure in studied data sets.
The development of an evidence-based inference engine that can substantially interpret the data at hand and

  • convert it in real time to a “knowledge-based opinion”

could improve clinical decision-making by incorporating into the model

  • multiple complex clinical features as well as onset and duration .

An example of a difficult area for clinical problem solving is found in the diagnosis of Systemic Inflammatory Response Syndrome (SIRS) and associated sepsis. SIRS is a costly diagnosis in hospitalized patients.   Failure to diagnose it in a timely manner increases the financial and safety hazard.  The early diagnosis of SIRS/sepsis is made by the application of defined criteria by the clinician.

  • temperature
  • heartrate
  • respiratory rate and
  • WBC count

The application of those clinical criteria, however, defines the condition after it has developed, leaving unanswered the hope for

  • a reliable method for earlier diagnosis of SIRS.

The early diagnosis of SIRS may possibly be enhanced by the measurement of proteomic biomarkers, including

  • transthyretin
  • C-reactive protein
  • procalcitonin
  • mean arterial pressure

Immature granulocyte (IG) measurement has been proposed as a

  • readily available indicator of the presence of granulocyte precursors (left shift).

The use of such markers, obtained by automated systems in conjunction with innovative statistical modeling, provides

  • a promising support to early accurate decision making.

Such a system aims to reduce medical error by utilizing

  • the conjoined syndromic features of disparate data elements .

How we frame our expectations is important. It determines

  • the data we collect to examine the process.

In the absence of data to support an assumed benefit, there is no proof of validity at whatever cost.

Potential arenas of benefit include:

  • hospital operations
  • nonhospital laboratory studies
  • companies in the diagnostic business
  • planners of health systems

The problem stated by LL  WEED in “Idols of the Mind” (Dec 13, 2006):
“ a root cause of a major defect in the health care system is that, while we falsely admire and extol the intellectual powers of highly educated physicians, we do not search for the external aids their minds require.” Hospital information technology (HIT) use has been focused on information retrieval, leaving

  • the unaided mind burdened with information processing.

We deal with problems in the interpretation of data presented to the physician, and how the situation could be improved through better

  • design of the software that presents data .

The computer architecture that the physician uses to view the results is more often than not presented

  • as the designer would prefer, and not as the end-user would like.

In order to optimize the interface for physician, the system could have a “front-to-back” design, with the call up for any patient

  • A dashboard design that presents the crucial information that the physician would likely act on in an easily accessible manner
  • Each item used has to be closely related to a corresponding criterion needed for a decision.

Feature Extraction.

Eugene Rypka contributed greatly to clarifying the extraction of features in a series of articles, which

  • set the groundwork for the methods used today in clinical microbiology.

The method he describes is termed S-clustering, and

  • will have a significant bearing on how we can view laboratory data.

He describes S-clustering as extracting features from endogenous data that

  • amplify or maximize structural information to create distinctive classes.

The method classifies by taking the number of features with sufficient variety to generate maps.

The mapping is done by

  • a truth table NxN of messages and choices
  • each variable is scaled to assign values for each message choice.

For example, the message for an antibody titer would be converted from 0 + ++ +++ to 0 1 2 3.

Even though there may be a large number of measured values, the variety is reduced by this compression, even though it may represent less information.

The main issue is

  • how a combination of variables falls into a table to convey meaningful information.

We are concerned with

  • accurate assignment into uniquely variable groups by information in test relationships.

One determines the effectiveness of each variable by its contribution to information gain in the system. The reference or null set is the class having no information.  Uncertainty in assigning to a classification can be countered by providing sufficient information.

One determines the effectiveness of each variable by its contribution to information gain in the system. The possibility for realizing a good model for approximating the effects of factors supported by data used

  • for inference owes much to the discovery of Kullback-Liebler distance or “information”, and Akaike
  • found a simple relationship between K-L information and Fisher’s maximized log-likelihood function.

In the last 60 years the application of entropy comparable to

  • the entropy of physics, information, noise, and signal processing,
  • developed by Shannon, Kullback, and others
  • integrated with modern statistics,
  • as a result of the seminal work of Akaike, Leo Goodman, Magidson and Vermunt, and work by Coifman

Akaike pioneered recognition that the choice of model influence results in a measurable manner. In particular, a larger number of variables promotes further explanations of variance, such that a model selection criterion is important that penalizes for the number of variables when success is measured by explanation of variance.

Gil David et al. introduced an AUTOMATED processing of the data available to the ordering physician and

  • can anticipate an enormous impact in diagnosis and treatment of perhaps half of the top 20 most common
  • causes of hospital admission that carry a high cost and morbidity.

For example:

  1. anemias (iron deficiency, vitamin B12 and folate deficiency, and hemolytic anemia or myelodysplastic syndrome);
  2. pneumonia; systemic inflammatory response syndrome (SIRS) with or without bacteremia;
  3. multiple organ failure and hemodynamic shock;
  4. electrolyte/acid base balance disorders;
  5. acute and chronic liver disease;
  6. acute and chronic renal disease;
  7. diabetes mellitus;
  8. protein-energy malnutrition;
  9. acute respiratory distress of the newborn;
  10. acute coronary syndrome;
  11. congestive heart failure;
  12. hypertension
  13. disordered bone mineral metabolism;
  14. hemostatic disorders;
  15. leukemia and lymphoma;
  16. malabsorption syndromes; and
  17. cancer(s)[breast, prostate, colorectal, pancreas, stomach, liver, esophagus, thyroid, and parathyroid].
  18. endocrine disorders
  19. prenatal and perinatal diseases

Rudolph RA, Bernstein LH, Babb J: Information-Induction for the diagnosis of
myocardial infarction. Clin Chem 1988;34:2031-2038.

Bernstein LH (Chairman). Prealbumin in Nutritional Care Consensus Group.

Measurement of visceral protein status in assessing protein and energy
malnutrition: standard of care. Nutrition 1995; 11:169-171.

Bernstein LH, Qamar A, McPherson C, Zarich S, Rudolph R. Diagnosis of myocardial infarction:
integration of serum markers and clinical descriptors using information theory.
Yale J Biol Med 1999; 72: 5-13.

Kaplan L.A.; Chapman J.F.; Bock J.L.; Santa Maria E.; Clejan S.; Huddleston D.J.; Reed R.G.;
Bernstein L.H.; Gillen-Goldstein J. Prediction of Respiratory Distress Syndrome using the
Abbott FLM-II amniotic fluid assay. The National Academy of Clinical Biochemistry (NACB)
Fetal Lung Maturity Assessment Project.  Clin Chim Acta 2002; 326(8): 61-68.

Bernstein LH, Qamar A, McPherson C, Zarich S. Evaluating a new graphical ordinal logit method
(GOLDminer) in the diagnosis of myocardial infarction utilizing clinical features and laboratory
data. Yale J Biol Med 1999; 72:259-268.

Bernstein L, Bradley K, Zarich SA. GOLDmineR: Improving models for classifying patients with
chest pain. Yale J Biol Med 2002; 75, pp. 183-198.

Ronald Raphael Coifman and Mladen Victor Wickerhauser. Adapted Waveform Analysis as a Tool for Modeling, Feature Extraction, and Denoising. Optical Engineering, 33(7):2170–2174, July 1994.

R. Coifman and N. Saito. Constructions of local orthonormal bases for classification and regression.
C. R. Acad. Sci. Paris, 319 Série I:191-196, 1994.

Realtime Clinical Expert Support and validation System

We have developed a software system that is the equivalent of an intelligent Electronic Health Records Dashboard that provides empirical medical reference and suggests quantitative diagnostics options. The primary purpose is to gather medical information, generate metrics, analyze them in realtime and provide a differential diagnosis, meeting the highest standard of accuracy. The system builds its unique characterization and provides a list of other patients that share this unique profile, therefore

  • utilizing the vast aggregated knowledge (diagnosis, analysis, treatment, etc.) of the medical community.
  • The main mathematical breakthroughs are provided by accurate patient profiling and inference methodologies
  • in which anomalous subprofiles are extracted and compared to potentially relevant cases.

As the model grows and its knowledge database is extended, the diagnostic and the prognostic become more accurate and precise.
We anticipate that the effect of implementing this diagnostic amplifier would result in

  • higher physician productivity at a time of great human resource limitations,
  • safer prescribing practices,
  • rapid identification of unusual patients,
  • better assignment of patients to observation, inpatient beds,
    intensive care, or referral to clinic,
  • shortened length of patients ICU and bed days.

The main benefit is a

  1. real time assessment as well as
  2. diagnostic options based on comparable cases,
  3. flags for risk and potential problems

as illustrated in the following case acquired on 04/21/10. The patient was diagnosed by our system with severe SIRS at a grade of 0.61 .

Graphical presentation of patient status

The patient was treated for SIRS and the blood tests were repeated during the following week. The full combined record of our system’s assessment of the patient, as derived from the further hematology tests, is illustrated below. The yellow line shows the diagnosis that corresponds to the first blood test (as also shown in the image above). The red line shows the next diagnosis that was performed a week later.

Progression changes in patient ICU stay with SIRS

The MISSIVE(c) system, by Justin Pearlman, is an alternative approach that includes not only automated data retrieval and reformatting of data for decision support, but also an integrated set of tools to speed up analysis, structured for quality and error reduction, couplled to facilitated report generation, incorporation of just-in-time knowledge and group expertise, standards of care, evidence-based planning, and both physician and patient instruction.

See also in Pharmaceutical Intelligence:

The Cost Burden of Disease: U.S. and Michigan.CHRT Brief. January 2010. @www.chrt.org

The National Hospital Bill: The Most Expensive Conditions by Payer, 2006. HCUP Brief #59.

Rudolph RA, Bernstein LH, Babb J: Information-Induction for the diagnosis of myocardial infarction. Clin Chem 1988;34:2031-2038.

Bernstein LH, Qamar A, McPherson C, Zarich S, Rudolph R. Diagnosis of myocardial infarction:
integration of serum markers and clinical descriptors using information theory.
Yale J Biol Med 1999; 72: 5-13.

Kaplan L.A.; Chapman J.F.; Bock J.L.; Santa Maria E.; Clejan S.; Huddleston D.J.; Reed R.G.;
Bernstein L.H.; Gillen-Goldstein J. Prediction of Respiratory Distress Syndrome using the Abbott FLM-II amniotic fluid assay. The National Academy of Clinical Biochemistry (NACB) Fetal Lung Maturity Assessment Project.  Clin Chim Acta 2002; 326(8): 61-68.

Bernstein LH, Qamar A, McPherson C, Zarich S. Evaluating a new graphical ordinal logit method (GOLDminer) in the diagnosis of myocardial infarction utilizing clinical features and laboratory
data. Yale J Biol Med 1999; 72:259-268.

Bernstein L, Bradley K, Zarich SA. GOLDmineR: Improving models for classifying patients with chest pain. Yale J Biol Med 2002; 75, pp. 183-198.

Ronald Raphael Coifman and Mladen Victor Wickerhauser. Adapted Waveform Analysis as a Tool for Modeling, Feature Extraction, and Denoising.
Optical Engineering 1994; 33(7):2170–2174.

R. Coifman and N. Saito. Constructions of local orthonormal bases for classification and regression. C. R. Acad. Sci. Paris, 319 Série I:191-196, 1994.

W Ruts, S De Deyne, E Ameel, W Vanpaemel,T Verbeemen, And G Storms. Dutch norm data for 13 semantic categoriesand 338 exemplars. Behavior Research Methods, Instruments,
& Computers 2004; 36 (3): 506–515.

De Deyne, S Verheyen, E Ameel, W Vanpaemel, MJ Dry, WVoorspoels, and G Storms.  Exemplar by feature applicability matrices and other Dutch normative data for semantic
concepts.  Behavior Research Methods 2008; 40 (4): 1030-1048

Landauer, T. K., Ross, B. H., & Didner, R. S. (1979). Processing visually presented single words: A reaction time analysis [Technical memorandum].  Murray Hill, NJ: Bell Laboratories.
Lewandowsky , S. (1991).

Weed L. Automation of the problem oriented medical record. NCHSR Research Digest Series DHEW. 1977;(HRA)77-3177.

Naegele TA. Letter to the Editor. Amer J Crit Care 1993;2(5):433.

Sheila Nirenberg/Cornell and Chethan Pandarinath/Stanford, “Retinal prosthetic strategy with the capacity to restore normal vision,” Proceedings of the National Academy of Sciences.

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

http://pharmaceuticalintelligence.com/2012/08/13/the-automated-second-opinion-generator/

http://pharmaceuticalintelligence.com/2012/09/21/the-electronic-health-record-how-far-we-
have-travelled-and-where-is-journeys-end/

http://pharmaceuticalintelligence.com/2013/02/18/the-potential-contribution-of-
informatics-to-healthcare-is-more-than-currently-estimated/

http://pharmaceuticalintelligence.com/2013/05/04/cardiovascular-diseases-decision-support-
systems-for-disease-management-decision-making/?goback=%2Egde_4346921_member_239739196

http://pharmaceuticalintelligence.com/2012/08/13/demonstration-of-a-diagnostic-clinical-
laboratory-neural-network-agent-applied-to-three-laboratory-data-conditioning-problems/

http://pharmaceuticalintelligence.com/2012/12/17/big-data-in-genomic-medicine/

http://pharmaceuticalintelligence.com/2013/02/13/cracking-the-code-of-human-life-
the-birth-of-bioinformatics-and-computational-genomics/

http://pharmaceuticalintelligence.com/2013/04/28/genetics-of-conduction-disease-
atrioventricular-av-conduction-disease-block-gene-mutations-transcription-excitability-
and-energy-homeostasis/

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

http://pharmaceuticalintelligence.com/2012/08/14/regression-a-richly-textured-method-
for-comparison-and-classification-of-predictor-variables/

http://pharmaceuticalintelligence.com/2012/08/02/diagnostic-evaluation-of-sirs-by-
immature-granulocytes/

http://pharmaceuticalintelligence.com/2012/08/01/automated-inferential-diagnosis-
of-sirs-sepsis-septic-shock/

http://pharmaceuticalintelligence.com/2012/08/12/1815/

http://pharmaceuticalintelligence.com/2012/08/15/1946/

http://pharmaceuticalintelligence.com/2013/05/13/vinod-khosla-20-doctor-included-speculations-
musings-of-a-technology-optimist-or-technology-will-replace-80-of-what-doctors-do/

http://pharmaceuticalintelligence.com/2013/05/05/bioengineering-of-vascular-and-tissue-models/

The Heart: Vasculature Protection – A Concept-based Pharmacological Therapy including THYMOSIN
Aviva Lev-Ari, PhD, RN 2/28/2013
http://pharmaceuticalintelligence.com/2013/02/28/the-heart-vasculature-protection-a-concept-
based-pharmacological-therapy-including-thymosin/

FDA Pending 510(k) for The Latest Cardiovascular Imaging Technology
Aviva Lev-Ari, PhD, RN 1/28/2013
http://pharmaceuticalintelligence.com/2013/01/28/fda-pending-510k-for-the-latest-
cardiovascular-imaging-technology/

PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not
Platelet Reactivity    Aviva Lev-Ari, PhD, RN 1/10/2013
http://pharmaceuticalintelligence.com/2013/01/10/pci-outcomes-increased-ischemic-risk-
associated-with-elevated-plasma-fibrinogen-not-platelet-reactivity/

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
http://pharmaceuticalintelligence.com/2013/01/03/the-acuity-pci-score-will-it-replace-four-
established-risk-scores-timi-grace-syntax-and-clinical-syntax/

Coronary artery disease in symptomatic patients referred for coronary angiography: Predicted by
Serum Protein Profiles    Aviva Lev-Ari, PhD, RN 12/29/2012
http://pharmaceuticalintelligence.com/2012/12/29/coronary-artery-disease-in-symptomatic-
patients-referred-for-coronary-angiography-predicted-by-serum-protein-profiles/

New Definition of MI Unveiled, Fractional Flow Reserve (FFR)CT for Tagging Ischemia
Aviva Lev-Ari, PhD, RN 8/27/2012
http://pharmaceuticalintelligence.com/2012/08/27/new-definition-of-mi-unveiled-
fractional-flow-reserve-ffrct-for-tagging-ischemia/

Related articles
Herceptin Fab (antibody) - light and heavy chains

Herceptin Fab (antibody) – light and heavy chains (Photo credit: Wikipedia)

Personalized Medicine

Personalized Medicine (Photo credit: Wikipedia)

Diagnostic of pathogenic mutations. A diagnost...

Diagnostic of pathogenic mutations. A diagnostic complex is a dsDNA molecule resembling a short part of the gene of interest, in which one of the strands is intact (diagnostic signal) and the other bears the mutation to be detected (mutation signal). In case of a pathogenic mutation, the transcribed mRNA pairs to the mutation signal and triggers the release of the diagnostic signal (Photo credit: Wikipedia)

Read Full Post »

Gene, Meis1, Regulates the Heart’s Ability to Regenerate after Injuries.

Posted in Genome Biology, Origins of Cardiovascular Disease, tagged , , , , , , on May 3, 2013| 1 Comment »

Reporter: Aviva Lev-Ari, PhD, RN

Gene found that regenerates heart tissue

DALLAS – April 17, 2013 – Researchers at UT Southwestern Medical Center have identified a specific gene that regulates the heart’s ability to regenerate after injuries.

Scientists led by Dr. Hesham Sadek have demonstrated that the gene Meis1 regulates the regenerative capability of newborn hearts.

Scientists led by Dr. Hesham Sadek have demonstrated that the gene Meis1 regulates the regenerative capability of newborn hearts.

The function of the gene, called Meis1, in the heart was not known previously. The findings of the UTSW investigation are available online in Nature.

“We found that the activity of the Meis1 gene increases significantly in heart cells soon after birth, right around the time heart muscle cells stop dividing. Based on this observation we asked a simple question: If the Meis1 gene is deleted from the heart, will heart cells continue to divide through adulthood? The answer is ‘yes’,” said Dr. Hesham Sadek, assistant professor of internal medicine in the division of cardiology, and senior author of the study.

In 2011, Dr. Sadek’s laboratory showed that the newborn mammalian heart is capable of a vigorous, regenerative response to injury through division of its own cells. As the newborn develops, the heart rapidly loses the ability to regenerate and to repair injuries such as heart attacks.

The research team demonstrated that deletion of Meis1 extended the proliferation period in the hearts of newborn mice, and also re-activated the regenerative process in the adult mouse heart without harmful effect on cardiac functions. This new finding demonstrates that Meis1 is a key factor in the regeneration process, and the understanding of the gene’s function may lead to new therapeutic options for adult heart regeneration. The findings also provide a possible alternative to current adult heart regeneration research, which focuses on the use of stem cells to replace damaged heart cells.

“Meis1 is a transcription factor, which acts like a software program that has the ability to control the function of other genes. In this case, we found that Meis1 controls several genes that normally act as brakes on cell division,” Dr. Sadek said. “As such, Meis1 could possibly be used as an on/off switch for making adult heart cells divide. If done successfully, this ability could introduce a new era in treatment for heart failure.”

According to the American Heart Association, almost 6 million people in the U.S. have heart failure, which occurs when the heart cannot pump enough blood and oxygen to support other organs. Heart disease is the leading cause of death for both men and women in the country, according to the Centers for Disease Control and Prevention.

The study received support from the American Heart Association, the Gilead Research Scholars Program in Cardiovascular Disease, the Foundation for Heart Failure Research, and the National Institutes of Health.

The co-first authors of the study are Dr. Ahmed I. Mahmoud, who is now a postdoctoral fellow at Harvard University; Dr. Fatih Kocabas, who is now a postdoctoral fellow at North American College; and Dr. Shalini A. Muralidhar, a postdoctoral research fellow II of internal medicine. Other researchers at UT Southwestern involved in the study are Wataru Kimura, a visiting senior researcher of internal medicine; Ahmed Koura, now a medical student at Ain Shams University in Egypt; Dr. Enzo Porrello, research fellow and faculty member at the University of Queensland in Australia; and Suwannee Thet, a research associate of internal medicine.

About UT Southwestern Medical Center
UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty includes many distinguished members, including five who have been awarded Nobel Prizes since 1985. Numbering more than 2,700, the faculty is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in 40 specialties to nearly 100,000 hospitalized patients and oversee more than 2.1 million outpatient visits a year.

Media Contact: Remekca Owens
214-648-9344
remekca.owens@utsouthwestern.edu

 http://www.utsouthwestern.edu/newsroom/news-releases/year-2013/april/heart-sadek.html?goback=.gde_4842427_member_233989854

Genetics: A gene of rare effect

A mutation that gives people rock-bottom cholesterol levels has led geneticists to what could be the next blockbuster heart drug.

09 April 2013
ADAPTED FROM: PETER DAZELEY/GETTY

When Sharlayne Tracy showed up at the clinical suite in the University of Texas (UT) Southwestern Medical Center in Dallas last January, the bandage wrapped around her left wrist was the only sign of anything medically amiss. The bandage covered a minor injury from a cheerleading practice led by Tracy, a 40-year-old African American who is an aerobics instructor, a mother of two and a college student pursuing a degree in business. “I feel like I’m healthy as a horse,” she said.

Indeed, Tracy’s well-being has been inspiring to doctors, geneticists and now pharmaceutical companies precisely because she is so normal. Using every tool in the modern diagnostic arsenal — from brain scans and kidney sonograms to 24-hour blood-pressure monitors and cognitive tests — researchers at the Texas medical centre have diagnostically sliced and diced Tracy to make sure that the two highly unusual genetic mutations she has carried for her entire life have produced nothing more startling than an incredibly low level of cholesterol in her blood. At a time when the target for low-density lipoprotein (LDL) cholesterol, more commonly called ‘bad cholesterol’, in Americans’ blood is less than 100 milligrams per decilitre (a level many people fail to achieve), Tracy’s level is just 14.

A compact woman with wide-eyed energy, Tracy (not her real name) is one of a handful of African Americans whose genetics have enabled scientists to uncover one of the most promising compounds for controlling cholesterol since the first statin drug was approved by the US Food and Drug Administration in 1987. Seven years ago, researchers Helen Hobbs and Jonathan Cohen at UT-Southwestern reported1 that Tracy had inherited two mutations, one from her father and the other from her mother, in a gene called PCSK9, effectively eliminating a protein in the blood that has a fundamental role in controlling the levels of LDL cholesterol. African Americans with similar mutations have a nearly 90% reduced risk of heart disease. “She’s our girl, our main girl,” says Barbara Gilbert, a nurse who has drawn some 8,000 blood samples as part of Cohen and Hobbs’ project to find genes important to cholesterol metabolism.

Of all the intriguing DNA sequences spat out by the Human Genome Project and its ancillary studies, perhaps none is a more promising candidate to have a rapid, large-scale impact on human health than PCSK9. Elias Zerhouni, former director of the US National Institutes of Health (NIH) in Bethesda, Maryland, calls PCSK9 an “iconic example” of translational medicine in the genomics era. Preliminary clinical trials have already shown that drugs that inhibit the PCSK9 protein — used with or without statins — produce dramatic reductions in LDL cholesterol (more than 70% in some patients). Half-a-dozen pharmaceutical companies — all aiming for a share of the global market for cholesterol-reducing drugs that could reach US$25 billion in the next five years according to some estimates — are racing to the market with drugs that mimic the effect of Tracy’s paired mutations.

Free interview

Stephen Hall talks about Sharlayne’s unusual condition and whether similar cases might lead to a new line of drugs.

Zerhouni, now an in-house champion of this class of drug as an executive at drug firm Sanofi, headquartered in Paris, calls the discovery and development of PCSK9 a “beautiful story” in which researchers combined detailed physical information about patients with shrewd genetics to identify a medically important gene that has made “super-fast” progress to the clinic. “Once you have it, boy, everything just lines up,” he says. And although the end of the PCSK9 story has yet to be written — the advanced clinical trials now under way could still be derailed by unexpected side effects — it holds a valuable lesson for genomic research. The key discovery about PCSK9‘s medical potential was made by researchers working not only apart from the prevailing scientific strategy of genome research over the past decade, but with an almost entirely different approach.

As for Tracy, who lives in the southern part of Dallas County, the implications of her special genetic status have become clear. “I really didn’t understand at first,” she admits. “But now I’m watching ads on TV [for cholesterol-lowering drugs], and it’s like, ‘Wow, I don’t have that problem’.”

A heart problem

Cardiovascular disease is — and will be for the foreseeable future, according to the World Health Organization — the leading cause of death in the world, and its development is intimately linked to elevated levels of cholesterol in the blood. Since their introduction, statin drugs have been widely used to lower cholesterol levels. But Jan Breslow, a physician and geneticist at Rockefeller University in New York, points out that up to 20% of patients cannot tolerate statins’ side effects, which include muscle pain and even forgetfulness. And in many others, the drugs simply don’t control cholesterol levels well enough.

The search for better treatments for heart disease gained fresh impetus after scientists published the draft sequence of the human genome in 2001. In an effort to identify the genetic basis of common ailments such as heart disease and diabetes, geneticists settled on a strategy based on the ‘common variant hypothesis’. The idea was that a handful of disease-related versions (or variants) of genes for each disease would be common enough — at a frequency of roughly 5% or so — to be detected by powerful analyses of the whole genome. Massive surveys known as genome-wide association studies compared the genomes of thousands of people with heart disease, for example, with those of healthy controls. By 2009, however, many scientists were lamenting the fact that although the strategy had identified many common variants, each made only a small contribution to the disease. The results for cardiovascular disease have been “pretty disappointing”, says Daniel Steinberg, a lipoprotein expert at the University of California, San Diego.

Single-minded: Helen Hobbs and Jonathan Cohen’s approach to heart-disease genetics yielded a target for drugs that could compete with statins.MISTY KEASLER/REDUX/EYEVINE

More than a decade earlier, in Texas, Hobbs and Cohen had taken the opposite tack. They had backgrounds in Mendelian, or single-gene, disorders, in which an extremely rare variant can have a big — often fatal — effect. They also knew that people with a particular Mendelian disorder didn’t share a single common mutation in the affected gene, but rather had a lot of different, rare mutations. They hypothesized that in complex disorders, many different rare variants were also likely to have a big effect, whereas common variants would have relatively minor effects (otherwise natural selection would have weeded them out). “Jonathan and I did not see any reason why it couldn’t be that rare variants cumulatively contribute to disease,” Hobbs says. To find these rare variants, the pair needed to compile detailed physiological profiles, or phenotypes, of a large general population. Cohen spoke of the need to “Mendelize” people — to compartmentalize them by physiological traits, such as extremely high or low cholesterol levels, and then look in the extreme groups for variations in candidate genes known to be related to the trait.

The pair make a scientific odd couple. Hobbs, who trained as an MD, is gregarious, voluble and driven. Cohen, a soft-spoken geneticist from South Africa, has a laid-back, droll manner and a knack for quantitative thinking. In 1999, they set out to design a population-based study that focused on physical measurements related to heart disease. Organized with Ronald Victor, an expert on high blood pressure also at UT Southwestern, and funded by the Donald W. Reynolds Foundation in Las Vegas, Nevada, the Dallas Heart Study assembled exquisitely detailed physiological profiles on a population of roughly 3,500 Dallas residents2. Crucially, around half of the participants in the study were African Americans, because the researchers wanted to probe racial differences in heart disease and high blood pressure. The team measured blood pressure, body mass index, heart physiology and body-fat distribution, along with a battery of blood factors related to cholesterol metabolism — triglycerides, high-density lipoprotein (HDL) cholesterol and LDL cholesterol. In the samples of blood, of course, they also had DNA from each and every participant.

As soon as the database was completed in 2002, Hobbs and Cohen tested their rare-variant theory by looking at levels of HDL cholesterol. They identified the people with the highest (95th percentile) and lowest (5th percentile) levels, and then sequenced the DNA of three genes known to be key to metabolism of HDL cholesterol. What they found, both in Dallas and in an independent population of Canadians, was that the number of mutations was five times higher in the low HDL group than in the high group3. This made sense, Cohen says, because most human mutations interfere with the function of genes, which would lead to the low HDL numbers. Published in 2004, the results confirmed that rare, medically important mutations could be found in a population subdivided into extreme phenotypes.

Armed with their extensive database of cardiovascular traits, Hobbs and Cohen could now dive back into the Dallas Heart Study whenever they had a new hypothesis about heart disease and, as Cohen put it, “interrogate the DNA”. It wasn’t long before they had an especially intriguing piece of DNA at which to look.

The missing link

In February 2003, Nabil Seidah, a biochemist at the Clinical Research Institute of Montreal in Canada, and his colleagues reported the discovery of an enigmatic protein4. Seidah had been working on a class of enzymes known collectively as proprotein convertases, and the researchers had identified what looked like a new member of the family, called NARC-1: neural apoptosis-regulated convertase 1.

“We didn’t know what it was doing, of course,” Seidah says. But the group established that the gene coding the enzyme showed activity in the liver, kidney and intestines as well as in the developing brain. The team also knew that in humans the gene mapped to a precise genetic neighbourhood on the short arm of chromosome 1.

That last bit of geographical information pointed Seidah to a group led by Catherine Boileau at the Necker Hospital in Paris. Her team had been following families with a genetic form of extremely high levels of LDL cholesterol known as familial hypercholesterolaemia, which leads to severe coronary artery disease and, often, premature death. Group member Marianne Abifadel had spent five fruitless years searching a region on the short arm of chromosome 1 for a gene linked to the condition. When Seidah contacted Boileau and told her that he thought NARC-1 might be the gene she was looking for, she told him, “You’re crazy”, Seidah recalls. Seidah bet her a bottle of champagne that he was correct; within two weeks, Boileau called back, saying: “I owe you three bottles.”

“The PCSK9 story is a terrific example of an up-and-coming pattern of translational research.”

In 2003, the Paris and Montreal groups reported that the French families with hypercholesterolaemia had one of two mutations in this newly discovered gene, and speculated that this might cause increased production of the enzyme5. Despite Seidah’s protests, the journal editors gave both the gene and its protein product a new name that fit with standard nomenclature: proprotein convertase subtilisin/kexin type 9, or PCSK9. At around the same time, Kara Maxwell in Breslow’s group at Rockefeller University6 and Jay Horton, a gastroenterologist at UT-Southwestern7 also independently identified the PCSK9 gene in mice and revealed its role in a previously unknown pathway regulating cholesterol8.

The dramatic phenotype of the French families told Hobbs that “this is an important gene”. She also realized that in genetics, mutations that knock out a function are much more common than ones that amplify function, as seemed to be the case with the French families. “So immediately I’m thinking, a loss-of-function mutation should manifest as a low LDL level,” she says. “Let’s go and see if that’s true.”

Going to extremes

Hobbs and Cohen had no further to look than in the extreme margins of people in the Dallas Heart Study. In quick order, they identified the highest and lowest LDL readings in four groups: black women, black men, white women and white men. They then resequenced the PCSK9 gene in the low-cholesterol groups, looking for mutations that changed the make-up of the protein.

They found seven African Americans with one of two distinct ‘nonsense’ mutations in PCSK9 — mutations that essentially aborted production of the protein. Then they went back and looked for the same mutations in the entire population. Just 2% of all black people in the Dallas study had either of the two PCSK9 mutations — and those mutations were each associated with a 40% reduction of LDL cholesterol in the blood9. (The team later detected a ‘missense mutation’ in 3% of white people, which impaired but did not entirely block production of the protein.) The frequency of the mutations was so low, Hobbs says, that they would never have shown up in a search for common variants.

When Hobbs and Cohen published their findings in 2005, they suggested that PCSK9 played a crucial part in regulating bad cholesterol, but said nothing about whether the mutations had any effect on heart disease. That evidence came later that year, when they teamed up with Eric Boerwinkle, a geneticist at the University of Texas Health Science Center in Houston, to look forPCSK9 mutations in the Atherosclerosis Risk in Communities (ARIC) study, a large prospective study of heart disease that had been running since 1987. To experts such as Steinberg, the results10 — published in early 2006 — were “mind-blowing”. African Americans in ARIC who had mutations in PCSK9 had 28% less LDL cholesterol and an 88% lower risk of developing heart disease than people without the mutations. White people with the less severe mutation in the gene had a 15% reduction in LDL and a 47% reduced risk of heart disease.

How did the gene exert such profound effects on LDL cholesterol levels? As researchers went on to determine11, the PCSK9 protein normally circulates in the bloodstream and binds to the LDL receptor, a protein on the surface of liver cells that captures LDL cholesterol and removes it from the blood. After binding with the receptor, PCSK9 escorts it into the interior of the cell, where it is eventually degraded. When there is a lot of PCSK9 (as in the French families), there are fewer LDL receptors remaining to trap and remove bad cholesterol from the blood. When there is little or no PCSK9 (as in the black people with mutations), there are more free LDL receptors, which in turn remove more LDL cholesterol.

“We didn’t understand why everybody wasn’t doing what we were doing.”

The UT-Southwestern group, meanwhile, went back into the community looking for family members who might carry additional PCSK9 mutations. In September 2004, Gilbert, the nurse known as ‘the cholesterol lady’ in south Dallas because of her frequent visits, knocked on the door of Sharlayne Tracy’s mother, an original member of the Dallas Heart Study. Gilbert tested Tracy, as well as her sister, brother and father. “They tested all of us, and I was the lowest,” Tracy says. Zahid Ahmad, a doctor working with Hobbs at UT-Southwestern, was one of the first to look at Tracy’s lab results. “Dr Zahid was in awe,” Tracy recalled. “He said, ‘You’re not supposed to be so healthy!’.”

It wasn’t just that her LDL cholesterol measured 14. As a person with two dysfunctional copies of the gene — including a new type of mutation — Tracy was effectively a human version of a knockout mouse. The gene had been functionally erased from her genome, and PCSK9 was undetectable in her blood without any obvious untoward effects. The genomics community might have been a little slow to understand the significance, Hobbs says, “but the pharmaceutical companies got it right away”.

The next statin?

This being biology, however, the road to the clinic was not completely smooth. The particular biology of PCSK9 has so far thwarted efforts to find a small molecule that would interrupt its interaction with the LDL receptor and that could be packaged in a pill. But the fact that the molecule operates outside cells means that it is vulnerable to attack by monoclonal antibodies — one of the most successful (albeit most expensive) forms of biological medicine.

The results of early clinical trials have caused a stir. Regeneron Pharmaceuticals of Tarrytown, New York, collaborating with Sanofi, published phase II clinical-trial results12 last October showing that patients with high LDL cholesterol levels who had injections every two weeks of an anti-PCSK9 monoclonal antibody paired with a high-dose statin saw their LDL cholesterol levels fall by 73%; by comparison, patients taking high-dose statins alone had a decrease of just 17%. Last November, Regeneron and Sanofi began to recruit 18,000 patients for phase III trials that will test the ability of their therapy to cut cardiovascular events, including heart attacks and stroke. Amgen of Thousand Oaks, California, has also launched several phase III trials of its own monoclonal antibody after it reported similarly promising results13. Among other companies working on PCSK9-based therapies are Pfizer headquartered in New York, Roche based in Basel, Switzerland, and Alnylam Pharmaceuticals of Cambridge, Massachusetts. (Hobbs previously consulted for Regeneron and Pfizer, and now sits on the corporate board of Pfizer.)

Not everyone is convinced that a huge market awaits this class of cholesterol-lowering drugs. Tony Butler, a financial analyst at Barclays Capital in New York, acknowledges the “beautiful biology” of the PCSK9 story, but wonders if the expense of monoclonal drugs — and a natural reluctance of both patients and doctors to use injectable medicines — will constrain potential sales. “I have no idea what the size of the market may be,” he says.

“Everything hinges on the phase III side effects,” says Steinberg. So far, the main side effects reported have been minor, such as reactions at the injection site, diarrhoea and headaches. But animal experiments have raised potential red flags: the Montreal lab reported in 2006 that knocking out the gene in zebrafish is lethal to embryos14. That is why the case of Tracy was “very, very helpful” to drug companies, says Hobbs. Although her twin mutations have essentially deprived her of PCSK9 throughout her life, doctors have found nothing abnormal about her.

That last point may revive a debate in the cardiology community: should drug therapy to lower cholesterol levels, including statins and the anti-PCSK9 medicines, if they pan out, be started much earlier in patients than their 40s or 50s? That was the message Steinberg took from the people withPCSK9 mutations in the ARIC study — once he got over his shock at the remarkable health effects. “My first reaction was, ‘This must be wrong. How could that be?’And then it hit me — these people had low LDL from the day they were born, and that makes all the difference.” Steinberg argues that cardiologists “should get off our bums” and reach a consensus about beginning people on cholesterol-lowering therapy in their early thirties. But Breslow, a former president of the American Heart Association, cautions against being too aggressive too soon. “Let’s start out with the high-risk individuals and see how they do,” he says.

Not long after Hobbs and Cohen published their paper in 2006, they began to get invited to give keynote talks at major cardiology meetings. Soon after, the genetics community began to acknowledge the strength of their approach. In autumn 2007, then-NIH director Zerhouni organized a discussion at the annual meeting of the institutes’ directors to raise the profile of the rare-variant approach and contrast it with genome-wide studies. “Obviously, the two approaches are opposed to each other, and the question was, what was the relative value of each?” says Zerhouni. “I thought the PCSK9 story was a terrific example of an up-and-coming pattern of translational research” — indeed, he adds, “a harbinger of things to come”.

Hobbs and Cohen might not have found their gene if they had not had a hunch about where to look, but improved sequencing technology and decreasing costs now allow genomicists to incorporate the rare variant approach and to mount large-scale sweeps in search of such variants. “Gene sequencing is getting cheap enough that if there’s another gene like PCSK9 out there, you could probably find it genome-wide,” says Jonathan Pritchard, a population biologist at the University of Chicago, Illinois.

“What was amazing to us,” says Hobbs, “was that the genome project was spending all this time, energy, effort sequencing people, and they weren’t phenotyped, so there was no potential for discovery. We didn’t understand, and couldn’t understand, why everybody wasn’t doing what we were doing. Particularly when we started making discoveries.”

Nature

 496,

152–155

(11 April 2013)

doi:10.1038/496152a

References

  1. Zhao, Z. et al. Am. J. Hum. Genet. 79, 514–523 (2006).

    Show context

  2. Victor, R. G. et al. Am. J. Cardiol. 93, 1473–1480 (2004).

    Show context

  3. Cohen, J. C. et al. Science 305, 869–872 (2004).

    Show context

  4. Seidah, N. G. et al. Proc. Natl Acad. Sci. USA 100, 928–933 (2003).

    Show context

  5. Abifadel, M. et al. Nature Genet. 34, 154–156 (2003).

    Show context

  6. Maxwell, K. N., Soccio, R. E., Duncan, E. M., Sehayek, E. & Breslow, J. L. J. Lipid Res. 44,2109–2119 (2003).

    Show context

  7. Horton, J. D. et al. Proc. Natl Acad. Sci. USA 100, 12027–12032 (2003).

    Show context

  8. Maxwell, K. N. & Breslow, J. L. Proc. Natl Acad. Sci. USA 101, 7100–7105 (2004).

    Show context

  9. Cohen, J. et al. Nature Genet. 37, 161–165 (2005).

    Show context

  10. Cohen, J. C., Boerwinkle, E., Mosley, T. H. Jr & Hobbs, H. H. N. Engl. J. Med. 354, 1264–1272(2006).

    Show context

  11. Horton, J. D., Cohen, J. C. & Hobbs, H. H. J. Lipid Res. 50, S172–S177 (2009).

    Show context

  12. Roth, E. M., McKenney, J. M., Hanotin, C., Asset, G. & Stein, E. A. N. Engl. J. Med. 367,1891–1900 (2012).

    Show context

  13. Koren, M. J. et al. Lancet 380, 1995–2006 (2012).

    Show context

  14. Poirier, S. et al. J. Neurochem. 98, 838–850 (2006).

    Show context

Read Full Post »

Economic Toll of Heart Failure in the US: Forecasting the Impact of Heart Failure in the United States – A Policy Statement From the American Heart Association

Posted in Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, Health Law & Patient Safety, Medical Devices R&D and Inventions, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Scientist: Career considerations, Statistical Methods for Research Evaluation, Stem Cells for Regenerative Medicine, Systemic Inflammatory Response Related Disorders, tagged , on April 25, 2013| 6 Comments »

Economic Toll of Heart Failure in the US: Forecasting the Impact of Heart Failure in the United States – A Policy Statement From the American Heart Association

Reporter: Aviva Lev-Ari, PhD, RN

 

  • AHA Policy Statement

Forecasting the Impact of Heart Failure in the United States

A Policy Statement From the American Heart Association

  1. Paul A. Heidenreich, MD, MS, FAHA, Chair,

  2. Nancy M. Albert, PhD, RN, FAHA,
  3. Larry A. Allen, MD, MHS,
  4. David A. Bluemke, MD, PhD, FAHA,
  5. Javed Butler, MD, MPH, FAHA,
  6. Gregg C. Fonarow, MD, FAHA,
  7. John S. Ikonomidis, MD, PhD, FRCS(C), FAHA,
  8. Olga Khavjou, MA,
  9. Marvin A. Konstam, MD,
  10. Thomas M. Maddox, MD, MSc,
  11. Graham Nichol, MD, MPH, FRCP(C), FAHA,
  12. Michael Pham, MD, MPH,
  13. Ileana L. Piña, MD, MPH, FAHA,
  14. Justin G. Trogdon, PhD and
  15. on behalf of the American Heart Association Advocacy Coordinating Committee:
  • Council on Arteriosclerosis,
  • Thrombosis and Vascular Biology,
  • Council on Cardiovascular Radiology and Intervention,
  • Council on Clinical Cardiology,
  • Council on Epidemiology and Prevention, and
  • Stroke Council

Abstract

Background—Heart failure (HF) is an important contributor to both the burden and cost of national healthcare expenditures, with more older Americans hospitalized for HF than for any other medical condition. With the aging of the population, the impact of HF is expected to increase substantially.

Methods and Results—We estimated future costs of HF by adapting a methodology developed by the American Heart Association to project the epidemiology and future costs of HF from 2012 to 2030 without double counting the costs attributed to comorbid conditions. The model assumes that HF prevalence will remain constant by age, sex, and race/ethnicity and that rising costs and technological innovation will continue at the same rate.

By 2030,

  • >8 million people in the United States (1 in every 33) will have HF.
  • Between 2012 and 2030, real (2010$) total direct medical costs of HF are projected to increase from $21 billion to $53 billion.
  • Total costs, including indirect costs for HF, are estimated to increase from $31 billion in 2012 to $70 billion in 2030.
  • If one assumes all costs of cardiac care for HF patients are attributable to HF (no cost attribution to comorbid conditions), the 2030 projected cost estimates of treating patients with HF will be 3-fold higher ($160 billion in direct costs).

Conclusions—The estimated prevalence and cost of care for HF will increase markedly because of aging of the population. Strategies to prevent HF and improve the efficiency of care are needed.

Key Words:

http://circheartfailure.ahajournals.org/content/early/2013/04/24/HHF.0b013e318291329a.abstract

15 page PDF, at the below link

http://circheartfailure.ahajournals.org/content/early/2013/04/24/HHF.0b013e318291329a.full.pdf+html?sid=ad1efd74-a4e1-45b0-8a47-350e85435487

REFERENCE

Four Policy Statement From the American Heart Association

  1. AHA Policy StatementForecasting the Impact of Heart Failure in the United States: A Policy Statement From the American Heart Association

    • Paul A. Heidenreich,
    • Nancy M. Albert,
    • Larry A. Allen,
    • David A. Bluemke,
    • Javed Butler,
    • Gregg C. Fonarow,
    • John S. Ikonomidis,
    • Olga Khavjou,
    • Marvin A. Konstam,
    • Thomas M. Maddox,
    • Graham Nichol,
    • Michael Pham,
    • Ileana L. Piña,
    • and Justin G. Trogdon

    Circ Heart Fail. 2013;published online before print April 24 2013,doi:10.1161/HHF.0b013e318291329a

    …American Heart Association. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations…and improve the efficiency of care are needed. AHA Scientific Statements|heart failure|
  2. Select this article

    Special ReportStatement Regarding the Pre and Post Market Assessment of Durable, Implantable Ventricular Assist Devices in the United States

    • Michael A. Acker,
    • Francis D. Pagani,
    • Wendy Gattis Stough,
    • Douglas L. Mann,
    • Mariell Jessup,
    • Robert Kormos,
    • Mark S. Slaughter,
    • Timothy Baldwin,
    • Lynne Stevenson,
    • Keith D. Aaronson,
    • Leslie Miller,
    • David Naftel,
    • Clyde Yancy,
    • Joseph Rogers,
    • Jeffrey Teuteberg,
    • Randall C. Starling,
    • Bartley Griffith,
    • Steven Boyce,
    • Stephen Westaby,
    • Elizabeth Blume,
    • Peter Wearden,
    • Robert Higgins,
    • and Michael Mack

    Circ Heart Fail. 2013;6:e1-e11, published online before print November 12 2012,doi:10.1161/HHF.0b013e318279f6b5

    …wolterskluwer.com . Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations…of Mechanically Assisted Circulatory Support.AHA Scientific Statements|heart-assist device|heart failure|BTC…
  3. Select this article

    Special ReportStatement Regarding the Pre and Post Market Assessment of Durable, Implantable Ventricular Assist Devices in the United States: Executive Summary

    • Michael A. Acker,
    • Francis D. Pagani,
    • Wendy Gattis Stough,
    • Douglas L. Mann,
    • Mariell Jessup,
    • Robert Kormos,
    • Mark S. Slaughter,
    • Timothy Baldwin,
    • Lynne Stevenson,
    • Keith D. Aaronson,
    • Leslie Miller,
    • David Naftel,
    • Clyde Yancy,
    • Joseph Rogers,
    • Jeffrey Teuteberg,
    • Randall C. Starling,
    • Bartley Griffith,
    • Steven Boyce,
    • Stephen Westaby,
    • Elizabeth Blume,
    • Peter Wearden,
    • Robert Higgins,
    • and Michael Mack

    Circ Heart Fail. 2013;6:145-150, published online before print November 12 2012,doi:10.1161/HHF.0b013e318279f55d

    …wolterskluwer.com . Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations…of Mechanically Assisted Circulatory Support.AHA Scientific Statements|heart-assist device|heart failure| Background…
  4. Select this article

    ACCF/AHA/HFSA Data and Survey ReportACCF/AHA/HFSA 2011 Survey Results: Current Staffing Profile of Heart Failure Programs, Including Programs That Perform Heart Transplant and Mechanical Circulatory Support Device Implantation: A Report of the ACCF Heart Failure and Transplant Committee, AHA Heart Failure and Transplantation Committee, and Heart Failure Society of America

    • Mariell Jessup,
    • Nancy M. Albert,
    • David E. Lanfear,
    • JoAnn Lindenfeld,
    • Barry M. Massie,
    • Mary Norine Walsh,
    • and Mark J. Zucker

    Circ Heart Fail. 2011;4:378-387, published online before print April 4 2011,doi:10.1161/HHF.0b013e3182186210

    …hired for a given practice volume. These survey results are an initial step in developing such standards. AHA Scientific Statements|heart failure|heart transplant|mechanical circulatory support device|staffing profile| 1. Introduction…

http://circheartfailure.ahajournals.org/search?fulltext=AHA+Scientific+Statements&sortspec=date&submit=Submit&andorexactfulltext=phrase

Read Full Post »

“In-hospital Cardiac Arrest” – Survival Improvement Achieved

Posted in Frontiers in Cardiology and Cardiovascular Disorders, HTN, Origins of Cardiovascular Disease, tagged , , , , on March 10, 2013| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

 

Very significant research results are reported below.

I witnessed the Rapid Response Team at MGH, on my night shift in August 2007 on a Cardiac Step-down Floor, performing CPR on a 71 year old female, a Cardiac patient. She was unsalvageable, her Attending Physician arrived to her bedside from home, two dozen professionals gathers in minuted from the Code Blue overhead announcement. The code cart was pushed to her room by myself and another Nurse. As the Physician who managed the Code left the patient room very disappointed, saying, “I have yet to see one successful resuscitation.”

In January 2009, as Supervisor of Kindred Long Term Care Acute Hospital at Waltham Hospital, 5th Floor, I performed CPR for a 69 year old male, a non Cardiac patient in Cardiac Arrest, Dr. Natov contacted the Code Blue, ACLS guidelines were followed and Patient survived.

I am very encouraged to learn the Survival Improvement by CPR achieved after “In-hospital Cardiac Arrest” as I am reporting, below.

In-hospital Cardiac Arrest: No Longer ‘Unsalvageable’

By Jill Gormley
Feb 27, 2013
- Chest pain

In-hospital cardiac arrest accounts for approximately160,000 deaths in the U.S. every year—similar to deaths from lung cancer—and yet it receives little attention and limited research funding. Those studying this silent epidemic say that decreasing the morbidity and mortality associated with in-hospital cardiac arrest is attainable and should be a focus of every provider’s quality improvement efforts.

One of those researchers, Paul S. Chan, MD, of Saint Luke’s Health System in Kansas City, Mo., feels that paying more attention to preventing and responding appropriately to in-hospital cardiac arrest can make a huge impact. He cites the great leaps made in improving care for heart failure and MI over the past few decades, contending that similar strides can be made in improving survival after in-hospital cardiac arrest.

The American Heart Association has made in-hospital cardiac arrest a focus for quality improvement with its Get With the Guidelines-Resuscitation (GWTG-R) registry, which collects information about resuscitation cases from participating hospitals and offers feedback on resuscitative practices and outcomes. The registry also uses the information collected to develop evidence-based guidelines and best practices. Currently, more than 1,550 hospitals participate in the registry, and studies of outcomes using registry data indicate that attention to the problem is producing results.

Survival Is Improving

ACS-NSQIP = American College of SurgeonsNational Surgical Quality Improvement Program; CPR = cardiopulmonary resuscitation
Source: JAMA Surg 2013;148[1]:14-21

Studying adults who experienced in-hospital cardiac arrest and using acute resuscitation survival (rate of return of spontaneous circulation for at least 20 minutes) and survival to discharge as endpoints, Chan and colleagues found encouraging trends among hospitals participating in GWTG-R (N Engl J Med 2012;367:1912-1920). Survival to discharge improved from 13.7 percent in 2000 to 22.3 percent in 2009. Acute resuscitation survival improved from 42.7 percent to 54.1 percent over the same period, and post-resuscitation survival increased from 32 percent to 42.9 percent.

There are similar trends in the pediatric arena. Between 2 and 6 percent of children admitted to intensive care units experience in-hospital cardiac arrest every year. Survival rates are poor and survivors often are left with neurological impairment. But a study of urban teaching hospitals with pediatric residency or fellowship programs participating in GWTG-R showed improvement among this vulnerable population as well (Circ Cardiovasc Qual Outcomes 2013; 6:42-49). Survival to discharge increased from 14.3 percent in 2000 to 43.4 percent in 2009 and post-resuscitation survival increased from 42.9 percent to 81.2 percent over the same time period. The researchers found no significant change in the percentage of survivors who experienced neurological impairment.

Saket Girotra, MD, an interventional cardiologist at the University of Iowa Hospital and co-author with Chan of the adult and pediatric studies, suggests there are a number of factors supporting increased survival of in-hospital cardiac arrest. Prompt recognition of patient distress, quality of chest compressions, timely defibrillation when necessary, proper administration of optimal medication, the engagement of hospital leadership in organizing better resuscitation team coordination and improved aftercare stand out among them. “All these are likely contributors, but we don’t yet have data to tell us what is driving these improvements. That is the next step for research,” he says.

There is some evidence that length of resuscitation efforts has an impact on survival (Lancet 2012;380:1473-1481). Again working with the GWTG-R registry, researchers analyzed the duration of resuscitation attempts in non-survivors at more than 400 hospitals to determine the mean length of resuscitation attempts before termination of rescue efforts. Overall, the mean length was 12 minutes for survivors and 20 minutes for non-survivors. But the researchers noted substantial variation between hospitals, with the hospitals in the quartile

with the longest duration of resuscitation attempts (mean of 25 minutes) engaging in resuscitative efforts 50 percent longer than hospitals in the quartile with the shortest duration of resuscitation (mean of 16 minutes). They found that patients who had cardiac arrests within hospitals with longer mean resuscitation attempt times were more likely to survive than those whose arrests occurred in hospitals with shorter mean resuscitation times.

Another recent study by a different team of researchers looked at cardiopulmonary resuscitation in surgical patients, and identified a potentially potent weapon against in-hospital arrest and mortality—prevention. This study found that complications, especially pneumonia and sepsis, preceded the large majority of cardiac arrests in surgical patients (JAMA Surg 2013;148[1]:14-21). Survival among these patients was poor—overall mortality at 30 days was 71.6 percent—but the authors concluded that many of these deaths could have been avoided through prevention of complications and expedient diagnosis and treatment of complications when they occurred.

Misperceptions Impede Progress

The opinion that the in-hospital cardiac arrest patient is unsalvageable persists, according to Chan. “There is a perception of futility that these patients are very, very sick, that they are unlikely to survive and that if they do survive, they will be neurologically devastated. Twenty years ago, that may have been true in many cases, but our research is showing it’s not true anymore,” he says.

In-hospital cardiac arrest is now less likely to be a result of MI or to be related to cardiovascular disease than it was in 2000, according to the analyses of GWTG-R data. Patients suffering in-hospital cardiac arrest are younger than they were in 2000 and more likely to have septicemia or other infections, to have been on mechanical ventilation and to have received intravenous vasopressors.

“Also, and very significantly, is that most patients who survive to discharge leave the hospital with no or minor neurological disability,” says Girotra. The study on survival outcomes showed that in 2000 half the patients who survived to discharge left the hospital with severe or clinically significant neurological disability, but by 2009, that percentage had dropped to 38.8 percent.

The study on duration of resuscitation attempts also examined neurologic status among patients who survived to discharge, and showed that those who survived long resuscitation attempts fared no worse neurologically than those whose resuscitations were shorter.

Researchers are currently exploring costs associated with survival of in-hospital cardiac arrest, aftercare, readmission and other variables, compared with the costs of surviving heart failure. “We are trying to paint an accurate picture of these patients to determine the amount of resources it takes to care for them after survival, and whether the outlook for these patients is really as pessimistic as is sometimes thought,” Chan says.

More granular data are necessary to identify the drivers of increased survival of in-hospital cardiac arrest and Chan says there is a need for funding to study cardiac arrest as a disease process. “If we can pinpoint exactly what the high-performing hospitals are doing well, we can establish good guidelines and best practices,” Girotra says. “Then, perhaps, we will see the sort of improvement that we have seen in MI survival extend to these patients, at all hospitals.”

http://www.cardiovascularbusiness.com/topics/prevention/hospital-cardiac-arrest-no-longer-‘unsalvageable’?page=0%2C1

 

Read Full Post »

Renal Denervation Safe in Real-World Setting: Preliminary results from the Global SYMPLICITY registry, 5/2013

Posted in Bio Instrumentation in Experimental Life Sciences Research, Cell Biology, Signaling & Cell Circuits, Ecosystems & Industrial Concentration in the Medical Device Sector, Frontiers in Cardiology and Cardiovascular Disorders, HTN, Medical Devices R&D Investment, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Renal Denervation, tagged , , , , , , , , , , on January 14, 2013| 2 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 5/29, 2013

Renal Denervation Safe in Real-World Setting

By Todd Neale, Senior Staff Writer, MedPage Today

Published: May 25, 2013

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Action Points:

PARIS — May 21-24, 2013

Out in everyday practice, renal denervation with the Symplicity device safely lowers blood pressure in patients with hypertension, preliminary results from the Global SYMPLICITY registry showed.

The Global SYMPLICITY registry is part of the clinical program evaluating the Symplicity device. It has been approved for use in Europe and elsewhere but remains restricted to investigational use in the U.S. Medtronic, which makes the Symplicity device, announced on Thursday that it has completed enrollment in Symplicity HTN-3, the pivotal U.S. trial.

The registry has a targeted enrollment of about 5,000 patients from about 200 centers worldwide; 149 sites spread throughout Canada, Mexico, South America, Europe, Africa, the Middle East, Asia, and Australia have already started collecting data.

Any patient who receives renal denervation can be included in the registry, and thus the study will include patients with hypertension and other conditions associated with increased sympathetic activity, including heart failure, insulin resistance, atrial fibrillation, sleep apnea, and chronic kidney disease.

European Society of Cardiology‘s recently published consensus paper on renal denervation, which recommended treatment in patients with a systolic blood pressure of 160 mm Hg or higher (or at least 150 mm Hg for type 2 diabetics) who were taking at least three antihypertensive medications, including a diuretic.

SOURCE:

Expert consensus document from the European Society of Cardiology on catheter-based renal denervation

http://eurheartj.oxfordjournals.org/content/early/2013/04/25/eurheartj.eht154.extract

Most of the first 617 patients included the registry (60%) were treated in accordance with the European Society of Cardiology’s recently published consensus paper on renal denervation, above.

About one-fifth of the patients (22%) started with a systolic blood pressure of at least 180 mm Hg, which was the average baseline blood pressure in the Symplicity HTN-1 and HTN-2 trials.

The average starting blood pressure overall was 164/89 mm Hg, and patients were taking an average of 4.35 medications. Common comorbidities included diabetes (38.2%), renal disease (30.1%), sleep apnea (16.3%), a history of cardiac disease (49%), heart failure (9.3%), and atrial fibrillation (11.9%).

The registry data showed significant drops in blood pressure measured both in the office and with 24-hour ambulatory monitoring, although the reductions were smaller than those seen in the clinical trials.

That’s not surprising, according to Mahfoud, because out in everyday practice blood pressure is not recorded as appropriately as in a clinical trial setting and poor compliance to medication becomes more of an issue. In fact, he said, a recent study showed that 47% of patients with resistant hypertension were not adherent to their medication regimens.

Also contributing to the smaller reductions in the real-world population is the fact that the average starting blood pressure was lower than in the clinical trials, Mahfoud said, adding that it is known that renal denervation induces greater reductions in blood pressure among those with the highest readings initially.

Mahfoud reported receiving institutional grant/research support from Medtronic, St. Jude, Recor, and serving as a consultant for St. Jude, Medtronic, Boston Scientific, and Cordis. Medtronic makes the Symplicity renal denervation device.

 Primary source: European Association of Percutaneous Cardiovascular Interventions

SOURCE REFERENCE:

Mahfoud F, et al “Early results following renal denervation for treatment of hypertension in a real-world population: the Global SYMPLICITY registry” EuroPCR 2013.

Adverse Events:
Of the first 617 patients included in the registry, only two had vascular complications related to access during the procedure, and none had serious events stemming from delivery of the radiofrequency energy to the renal artery; the rate of vasospasm was 9%, according to Felix Mahfoud, MD, of Saarland University Medical Center in Homburg/Saar, Germany.Through 6 months of follow-up, there were two hospitalizations for hypertensive crisis, two myocardial infarctions, one new case of end-stage renal disease from nephrotoxic overdose, and one death that was not considered to be related to the procedure, he reported at the EuroPCR meeting here.The procedure was not only safe, but also effective at lowering blood pressure, with reductions in office-based readings ranging from 13/6 mm Hg among patients with a baseline systolic blood pressure of 140 mm Hg or higher to 28/18 mm Hg among those with a baseline systolic pressure of 180 mm Hg or higher at 3 months. The findings were similar at 6 months.

“The take-home message will be hopefully … that renal denervation is a safe procedure providing blood pressure lowering in patients with high blood pressure at baseline and that that procedure might have an impact on clinical outcomes,” Mahfoud said in an interview.

Positive Effects of Renal Denervation Ablation for Hypertension in Controlled Randomized SYMPLICITY HTN-2 Trial

Renal Nerve Ablation Effects on BP Lasting

Download Complimentary Source PDF 

By Chris Kaiser, Cardiology Editor, MedPage Today

Published: January 08, 2013
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Late-term results from a study of the safety and effectiveness of renal denervation to reduce hypertension mirrored positive results seen earlier in the randomized SYMPLICITY HTN-2 trial, researchers found.

The mean reduction in systolic blood pressure at 1 year post procedure was a significant 28.1 mmHg (P<0.001), similar to the mean 31.7 mmHg drop at 6 months (P=0.16 for the comparison), according to Murray Esler, MD, of the Baker IDI Heart and Diabetes Institute in Melbourne, Australia, and colleagues.

Those in the control group who crossed over to the intervention at 6 months also had a significant fall in systolic blood pressure from a mean 190 to 166 mmHg (P<0.001), researchers reported in the January issue of Circulation: Journal of the American Heart Association.

The increasing prevalence of hypertension is a worldwide phenomenon, with an estimated 1.56 billion predicted to be affected in 2025, the authors noted. Yet, many of these patients cannot control their blood pressure (with control being defined as a pressure <140/90 mmHg) even when taking three or more antihypertensive medications.

Esler and colleagues cited a 2005 study that found a range of 47% to 87% of people in North America and Europe whose blood pressure is not under control (Lancet 2005; 365: 217-223).

Renal denervation has shown promise in these patients who are refractory to medication. The percutaneous procedure uses energy such as radiofrequency waves to scar the renal artery in an attempt to disrupt the sympathetic nerves, thereby affecting blood pressure.

Three-year data from the nonrandomized SYMPLICITY HTN-1 study were in line with 2- and 1-year results, showing a mean drop of 33/19 mmHg associated with the intervention.

In the current study, researchers from the multi-center randomized controlled SYMPLICITY HTN-2 trial enrolled 106 patients with essential hypertension (systolic blood pressure ≥160 mmHg, or ≥150 mmHg for diabetics). Patients were taking at least three antihypertensive medications.

The initial 1-year data from the SYMPLICITY HTN-2 trial were reported at the 2012 American College of Cardiology meeting. The primary endpoint was a change in systolic blood pressure at 6 months. Also at the 6-month mark, patients in the control group were allowed to cross over and receive the treatment; they were then followed for 6 more months.

The 6-month data were based on 101 patients (49 in the treatment group versus 51 controls). The 1-year data were based on 47 patients in the primary treatment group and 35 per-protocol controls who crossed over. The crossover patients also had to have a systolic blood pressure of ≥160 mmHg.

The significant decrease of 28.1 mmHg in systolic blood pressure in the treatment arm at 1 year was matched by significant drops in diastolic blood pressure at 6 and 12 months, as well as in the crossover group at 6 months (P<0.001 for all).

The authors reported that 84% of initial denervation patients had a decrease of at least 10 mmHg at 6 months; at 1 year, the number was 79%. In the crossover group, that rate was 63% at 6 months.

Interestingly, there was no significant difference in the changes in medication — reduced dosage or fewer drugs — between the treatment arm and controls, despite the reduction in blood pressure for the treatment arm.

“These data further substantiate the safety of renal sympathetic denervation via delivery of controlled radiofrequency energy bursts,” Esler and colleagues concluded.

They also noted that renal function remained unchanged at both 6 and 12 months. A pilot study by the Melbourne group looking specifically at patients with chronic kidney disease found renal denervation to be safe in this population.

The limitations to the current study include the lack of 24-hour blood pressure monitoring and the lack of blinding among the staff measuring blood pressure. The investigators noted that the ongoing SYMPLICITY HTN-3 trial addresses these limitations.

This study was funded by Medtronic Ardian.

Esler and three co-authors reported receiving research support from Medtronic Ardian. During the conduct of the trial, senior author Sobotka was chief medical officer of Ardian, and was a medical adviser to Medtronic.

From the American Heart Association:

 SOURCE:

Other articles on this topic on this Open Access Online Scientific Journal:

Lev-Ari, A. (2012aa). Renal Sympathetic Denervation: Updates on the State of Medicine

http://pharmaceuticalintelligence.com/2012/12/31/renal-sympathetic-denervation-updates-on-the-state-of-medicine/

 

Lev-Ari, A. (2012U). Imbalance of Autonomic Tone: The Promise of Intravascular Stimulation of Autonomics

http://pharmaceuticalintelligence.com/2012/09/02/imbalance-of-autonomic-tone-the-promise-of-intravascular-stimulation-of-autonomics/

Lev-Ari, A. (2012C). Treatment of Refractory Hypertension via Percutaneous Renal Denervation

http://pharmaceuticalintelligence.com/2012/06/13/treatment-of-refractory-hypertension-via-percutaneous-renal-denervation/

Read Full Post »

Gene Therapy Into Healthy Heart Muscle: Reprogramming Scar Tissue In Damaged Hearts

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cardiac & Vascular Repair Tools Subsegment, Cell Biology, Signaling & Cell Circuits, Chemical Genetics, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Human Immune System in Health and in Disease, Molecular Genetics & Pharmaceutical, Origins of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Resident-cell-based, Stem Cells for Regenerative Medicine, tagged , , , , , , on January 9, 2013| 6 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

Scar Tissue In Damaged Hearts Reprogrammed By Gene Therapy Into Healthy Heart Muscle

Article Date: 08 Jan 2013 – 0:00 PST

A cocktail of three specific genes can reprogram cells in the scars caused by heart attacks into functioning muscle cells, and the addition of a gene that stimulates the growth of blood vessels enhances that effect, said researchers from Weill Cornell Medical College, Baylor College of Medicine and Stony Brook University Medical Center in a report that appears online in the Journal of the American Heart Association. 

“The idea of reprogramming scar tissue in the heart into functioning heart muscle was exciting,” said Dr. Todd K. Rosengart, chair of the Michael E. DeBakey Department of Surgery at BCM and the report’s corresponding author. “The theory is that if you have a big heart attack, your doctor can just inject these three genes into the scar tissue during surgery and change it back into heart muscle. However, in these animal studies, we found that even the effect is enhanced when combined with the VEGF gene.” 

“This experiment is a proof of principle,” said Dr. Ronald G. Crystal, chairman and professor of genetic medicine at Weill Cornell Medical College and a pioneer in gene therapy, who played an important role in the research. “Now we need to go further to understand the activity of these genes and determine if they are effective in even larger hearts.” 

During a heart attack, blood supply is cut off to the heart, resulting in the death of heart muscle. The damage leaves behind a scar and a much weakened heart. Eventually, most people who have had serious heart attacks will develop heart failure. 

Changing the scar into heart muscle would strengthen the heart. To accomplish this, during surgery, Rosengart and his colleagues transferred three forms of the vascular endothelial growth factor (VEGF) gene that enhances blood vessel growth or an inactive material (both attached to a gene vector) into the hearts of rats. Three weeks later, the rats received either Gata4, Mef 2c and Tbx5 (the cocktail of transcription factor genes called GMT) or an inactive material. (A transcription factor binds to specific DNA sequences and starts the process that translates the genetic information into a protein.) 

The GMT genes alone reduced the amount of scar tissue by half compared to animals that did not receive the genes, and there were more heart muscle cells in the animals that were treated with GMT. The hearts of animals that received GMT alone also worked better as defined by ejection fraction than those who had not received genes. (Ejection fraction refers to the percentage of blood that is pumped out of a filled ventricle or pumping chamber of the heart.) 

The hearts of the animals that had received both the GMT and the VEGF gene transfers had an ejection fraction four times greater than that of the animals that had received only the GMT transfer. 

Rosengart emphasizes that more work needs to be completed to show that the effect of the VEGF is real, but it has real promise as part of a new treatment for heart attack that would minimize heart damage. 

“We have shown both that GMT can effect change that enhances the activity of the heart and that the VEGF gene is effective in improving heart function even more,” said Dr. Crystal. 

The idea started with the notion of induced pluripotent stem cells – reprograming mature specialized cells into stem cells that are immature and can differentiate into different specific cells needed in the body. Dr. Shinya Yamanaka and Sir John B. Gurdon received the Nobel Prize in Medicine and Physiology for their work toward this goal this year. 

However, use of induced pluripotent stem cells has the potential to cause tumors. To get around that, researchers in Dallas and San Francisco used the GMT cocktail to reprogram the scar cells into cardiomyocytes (cells that become heart muscle) in the living animals. 

Now Rosengart and his colleagues have gone a step farther – encouraging the production of new blood vessels to provide circulation to the new cells.

REFERENCES:

Others who took part in this work include Megumi Mathison, Ronald Gersch, Ahmed Nasser, Sarit Lilo, Mallory Korman, Mitchell Fourman, Kenneth Shroyer, Jianchang Yang, Yupo Ma, all of Stony Brook University Medical Center and Neil Hackett of Weill Cornell Medical College.
Funding for this work came from the generosity of James and Lisa Cohen.
Weill Cornell Medical College

CITATIONS:

MLA

n.p. “Scar Tissue In Damaged Hearts Reprogrammed By Gene Therapy Into Healthy Heart Muscle.” Medical News Today. MediLexicon, Intl., 8 Jan. 2013. Web.
9 Jan. 2013. <http://www.medicalnewstoday.com/releases/254618.php>

APA

n.p. (2013, January 8). “Scar Tissue In Damaged Hearts Reprogrammed By Gene Therapy Into Healthy Heart Muscle.” Medical News Today. Retrieved from
http://www.medicalnewstoday.com/releases/254618.php.

SOURCE:

http://www.medicalnewstoday.com/releases/254618.php 

Read Full Post »

UPDATED: PLATO Trial on ACS: BRILINTA (ticagrelor) better than Plavix® (clopidogrel bisulfate): Lowering chances of having another heart attack

Posted in Aortic Valve: TAVR, TAVI vs Open Heart Surgery, Cell Biology, Signaling & Cell Circuits, Coagulation Therapy and Internal Bleeding, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, Mitral Valve: Repair and Replacement, Origins of Cardiovascular Disease, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, tagged , , , , , , , , , , on December 28, 2012| 3 Comments »

UPDATED: PLATO Trial on ACS: BRILINTA (ticagrelor) better than Plavix® (clopidogrel bisulfate): Lowering chances of having another heart attack

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 9/1/2019

Extended DAPT with Brilinta: No Benefit for Stable CAD in T2D

Substudy in those with prior PCI might identify group where bleeding tradeoff is worthwhile

PARIS — Ticagrelor (Brilinta) as part of a dual antiplatelet therapy (DAPT) regimen didn’t improve net outcomes for stable coronary artery disease (CAD) among type 2 diabetes patients, except perhaps in the setting of percutaneous coronary intervention (PCI), the THEMIS trial showed.

Adding the potent antiplatelet agent to aspirin reduced cardiovascular (CV) death, myocardial infarction (MI), or stroke (7.7% vs 8.5%, HR 0.90, 95% CI 0.81-0.99), reported Deepak Bhatt, MD, MPH, of Brigham and Women’s Hospital and Harvard Medical School in Boston, at the European Society of Cardiology (ESC) congress and online in the New England Journal of Medicine.

But it also increased

  • TIMI major bleeding (2.2% vs 1.0%, HR 2.32, 95% CI 1.82-2.94) and
  • intracranial hemorrhage (0.7% vs 0.5%, HR 1.71, 95% CI 1.18- 2.48) over aspirin alone, albeit
  • without more fatal bleeding (0.2% vs 0.1%, P=0.11).

The combined effect was neutral for the exploratory composite outcome of “irreversible harm” (death from any cause, MI, stroke, fatal bleeding, or intracranial hemorrhage 10.1% vs 10.8%, HR 0.93, 95% CI 0.86-1.02).

ESC session study discussant Colin Baigent, MD, of Oxford University in England, actually calculated 12 major bleeds for every eight events prevented.

“This is a consistent story: when we add an antiplatelet agent for risk reduction, we increase the risk of bleeding,” noted Richard Kovacs, MD, of Indiana University in Indianapolis and president of the American College of Cardiology.

THEMIS is the final part of a largely-disappointing PARTHENON development program for ticagrelor, he noted. “It hasn’t changed practice. …Will the main THEMIS trial change clinical practice? In my opinion, no.”

SOURCE

https://www.medpagetoday.com/meetingcoverage/esc/81925?xid=nl_mpt_ACC_Reporter_2019-09-01&eun=g5099207d2r

 

UPDATED on 10/4/2016

Soriot’s $3.5B Brilinta dream is dashed by yet another big trial flop for AstraZeneca

by john carroll
October 4, 2016 09:00 AM EDT
Updated: 09:33 AM

Brilinta, the drug failed to demonstrate a benefit over generic Plavix (clopidogrel) for peripheral artery disease. Back in March, the heart drug flopped in a large stroke study, unable to prove that it could beat aspirin. And Soriot can chalk up those expensive studies to proving Brilinta’s serious deficiencies.

“We don’t believe the goal of $3.5 billion is attainable. I think it would be unrealistic to believe that,” Ludovic Helfgott, head of AstraZeneca’s Brilinta business, told Reuters.

Brilinta brought in a total of $619 million last year after disappointing analysts repeatedly with lower-than-expected quarterly revenue.

Heart studies aren’t cheap. AstraZeneca recruited 13,500 patients for the EUCLID study, and it had enrolled close to that number for the earlier SOCRATES trial.

SOURCE

http://endpts.com/soriots-3-5b-brilinta-dream-is-dashed-by-yet-another-big-trial-flop-for-astrazeneca/?utm_medium=email&utm_campaign=75%20Dinner%20with%20Brent&utm_content=75%20Dinner%20with%20Brent+CID_8008d3b4f16d90576238cceef624d211&utm_source=ENDPOINTS%20emails&utm_term=Soriots%2035B%20Brilinta%20dream%20is%20dashed%20by%20yet%20another%20big%20trial%20flop%20for%20AstraZeneca

UPDATED on 9/4/2014

Prehospital Ticagrelor in ST-Segment Elevation Myocardial Infarction

Gilles Montalescot, M.D., Ph.D., Arnoud W. van ‘t Hof, M.D., Ph.D., Frédéric Lapostolle, M.D., Ph.D., Johanne Silvain, M.D., Ph.D., Jens Flensted Lassen, M.D., Ph.D., Leonardo Bolognese, M.D., Warren J. Cantor, M.D., Ángel Cequier, M.D., Ph.D., Mohamed Chettibi, M.D., Ph.D., Shaun G. Goodman, M.D., Christopher J. Hammett, M.B., Ch.B., M.D., Kurt Huber, M.D., Magnus Janzon, M.D., Ph.D., Béla Merkely, M.D., Ph.D., Robert F. Storey, M.D., D.M., Uwe Zeymer, M.D., Olivier Stibbe, M.D., Patrick Ecollan, M.D., Wim M.J.M. Heutz, M.D., Eva Swahn, M.D., Ph.D., Jean-Philippe Collet, M.D., Ph.D., Frank F. Willems, M.D., Ph.D., Caroline Baradat, M.Sc., Muriel Licour, M.Sc., Anne Tsatsaris, M.D., Eric Vicaut, M.D., Ph.D., and Christian W. Hamm, M.D., Ph.D. for the ATLANTIC Investigators

September 1, 2014DOI: 10.1056/NEJMoa1407024

BACKGROUND

The direct-acting platelet P2Y12 receptor antagonist ticagrelor can reduce the incidence of major adverse cardiovascular events when administered at hospital admission to patients with ST-segment elevation myocardial infarction (STEMI). Whether prehospital administration of ticagrelor can improve coronary reperfusion and the clinical outcome is unknown.

Full Text of Background…

METHODS

We conducted an international, multicenter, randomized, double-blind study involving 1862 patients with ongoing STEMI of less than 6 hours’ duration, comparing prehospital (in the ambulance) versus in-hospital (in the catheterization laboratory) treatment with ticagrelor. The coprimary end points were the proportion of patients who did not have a 70% or greater resolution of ST-segment elevation before percutaneous coronary intervention (PCI) and the proportion of patients who did not have Thrombolysis in Myocardial Infarction flow grade 3 in the infarct-related artery at initial angiography. Secondary end points included the rates of major adverse cardiovascular events and definite stent thrombosis at 30 days.

Full Text of Methods…

RESULTS

The median time from randomization to angiography was 48 minutes, and the median time difference between the two treatment strategies was 31 minutes. The two coprimary end points did not differ significantly between the prehospital and in-hospital groups. The absence of ST-segment elevation resolution of 70% or greater after PCI (a secondary end point) was reported for 42.5% and 47.5% of the patients, respectively. The rates of major adverse cardiovascular events did not differ significantly between the two study groups. The rates of definite stent thrombosis were lower in the prehospital group than in the in-hospital group (0% vs. 0.8% in the first 24 hours; 0.2% vs. 1.2% at 30 days). Rates of major bleeding events were low and virtually identical in the two groups, regardless of the bleeding definition used.

Full Text of Results…

CONCLUSIONS

Prehospital administration of ticagrelor in patients with acute STEMI appeared to be safe but did not improve pre-PCI coronary reperfusion. (Funded by AstraZeneca; ATLANTIC ClinicalTrials.gov number, NCT01347580.)

SOURCE

http://www.nejm.org/doi/full/10.1056/NEJMoa1407024?query=TOC

 

 

UPDATED on 2/7/2014

PLATO Controversy Hits the Wall Street Journal

February 05, 2014

NEW YORK, NY – The controversy surrounding the PLATOtrial of ticagrelor (Brilinta, AstraZeneca) continues unabated, according to a story published in the Wall Street Journal. Specifically, a sealed complaint filed in US district court in the District of Columbia by a researcher contends that the cardiovascular events in the study “may have been manipulated” [1].

Dr Victor Serebruany (HeartDrug Research Laboratories, Johns Hopkins University, Towson, MD), who has long been a thorn in the side of AstraZeneca and the PLATO investigators, filed the complaint under the False Claims Act, reports theWall Street Journal. The Journal notes that the US attorney’s office in Washington, DC, has contacted Serebruany and is currently investigating the clinical trial.As reported by heartwirein October 2013, the US Department of Justice issued a civil investigative demand from its civil division “seeking documents and information regarding PLATO.” AstraZeneca is complying with the request.

First reported by heart wirein 2009 , the PLATO trial was a positive study involving more 18 000 patients from 43 countries. PLATO investigators, led by Dr Lars Wallentin (Uppsala Clinical Research Center, Sweden), showed that treating acute coronary syndrome patients with ticagrelor significantly reduced the rate of MI, stroke, and cardiovascular death compared with patients taking clopidogrel. Results were presented at the European Society of Cardiology 2009 Congress and reported in the New England Journal of Medicine.

PLATO has been dogged by questions, including prior to approval. In the sealed complaint, Serebruany takes issue with a number of things, many of which have been reported previously. He alleges that the

  • number of clinical events among those taking clopidogrel was high compared with other studies, pointing out that the rate of all-cause death was 5.9% among clopidogrel-treated patients—nearly twice as high as earlier studies. In addition,
  • the sealed complaint documents the geographic discrepancies in the trial, noting there was a trend toward worse outcomes with ticagrelor at North American sites.The complaint also alleges that
  • an initial count of clinical events suggested the two drugs were equivalent, but adjudication by the Duke Clinical Research Institute attributed another 45 MIs to the clopidogrel group, which tipped the results in favor of ticagrelor. Other questions raised about the study include
  • site monitoring and timing of clinical events. Serebruany also alleges that
  • the trial may have unintentionally been unblinded because of the shape of clopidogrel’s “split capsules,” which would have enabled doctors and nurses to know which drug patients received.

AstraZeneca rebutted these issues, telling the Journal that it is cooperating with the government. It said it is confident in the integrity of the trial and noted the overall study showed the superiority of ticagrelor over clopidogrel. There is no evidence the trial was unblinded and researchers used the same standards when qualifying all clinical events, including MIs, they noted. In addition, the company said it is not possible to compare event rates with clopidogrel in PLATO with other studies because the patient populations differ.

The Journal reports that Serebruany became embroiled in the controversy when asked by the FDA‘s Dr Thomas Marciniak to advise the agency about the PLATO data in 2010. Marciniak, who led the FDA’s review of PLATO, called AstraZeneca’s submission on serious adverse events the “worst submission” he ever encountered. According to the submission, he noted, 12 patients reported their own deaths by telephone. Before approving ticagrelor, the FDA requested an additional analysis of PLATO, and it was eventually approved in the US in July 2011. Ticagrelor was approved in Europe in December 2010 and is authorized for use in more than 100 countries.

The Journal called Serebruany an expert in the antiplatelet field but said he is a “controversial figure,” partly because of his financial ties to industry and repeated criticisms of new drug approvals. Through HeartDrug Research, Serebruany has worked on prasugrel (Effient, Lily/Daiichi-Sankyo), a competing antiplatelet agent, but has also done work for AstraZeneca.

REFERENCE

Burton TM. Doctor challenges testing of AstraZeneca’s Brilinta. Wall Street Journal, February 2, 2014. Available here.

SOURCE

http://www.medscape.com/viewarticle/820236?nlid=47583_1984&src=wnl_edit_medn_card&uac=93761AJ&spon=2

UPDATED 3/28/2013

How AstraZeneca Will Use A Diagnostic To Market Its Blood Thinner

by Matthew Harper, Forbes Staff on 3/21/2013

Earlier today I wrote about how AstraZeneca is telling investors that its blood-thinner Brilinta, used to prevent second heart attacks, could be a multi-billion dollar drug, at least twice as big as Wall Street analysts expect. So far the drug has been a disappointment.

I wrote:

Another key data point Astra presented was that blood levels of troponin, a muscle protein released by the heart during a heart attack, predict which patients get the most benefit from Brilinta. This data is not in AstraZeneca’s label, but a spokeswoman said that she believed it would be something the company can market to doctors.

via Can Pascal Soriot Turn Around AstraZeneca? It May Come Down To One Drug – Forbes.

But will the Food and Drug Administration allow Astra to tell doctors that? Stratification using troponin is not in Brilinta’s FDA-approved label, and off-label promotion is illegal. But Ferguson says that communications about troponin will be allowed because all patients with high troponin are patients who would be included in the FDA-approved indication. He confirms that use of troponin testing will be part of the new marketing plan for Brilinta.

SOURCE:

http://www.forbes.com/sites/matthewherper/2013/03/21/how-astrazeneca-will-use-a-diagnostic-to-market-its-blood-thinner/

Can Pascal Soriot Turn Around AstraZeneca? It May Come Down To One Drug

by Matthew Herper, Forbes Staff on 3/21/2013

This morning in New York, new AstraZeneca chief executive Pascal Soriot is telling investors how he is going to turn around the company that has had the absolute worst track record in research and development among any big pharmaceutical firm. The plan is fairly wide-ranging and involves a lot of the steps one might expect:

  • new layoffs (2,300 jobs);
  • a re-focusing of research and development on three areas: heart disease and diabetes; oncology; and respiratory and inflammation;
  • new R&D initiatives involving Moderna, a biotech company, and the Karolinska Instutet;
  • moving the company’s headquarters to its R&D hub in Cambridge, U.K.;
  • re-focusing on emerging markets, where AZ already gets $6 billion in sales, especially China.

But the short-term key to delivering on his promises today seems to come down to a single drug: Brilinta, the Plavix competitor thatAstraZeneca introduced in 2011 which has so far disappointed, generating  just $324 $89 million in global sales last year. This is a medicine to prevent heart attacks and strokes in patients who suffer acute coronary syndrome, the condition that occurs after a heart attack or serious heart-related chest pain. It works by preventing the formation of blood clots.

Plavix was the second biggest drug in the world, with $6 billion in annual sales, but it is now generic. The conventional wisdom is that it will be difficult to compete with cheap generics. Brilinta is actually trailing Effient, a similar medicine from Eli Lilly, in usage. Wall Street consensus currently sees Brilinta growing to become a moderate-sized drug in 2018, with $1.3 billion in annual sales. But AstraZeneca is saying that it thinks Brilinta can be a multi-billion dollar product. Astra has confirmed that this means Brilinta will have to surpass Effient. The newer drugs also cause more bleeding than Plavix.

What is the company’s argument? In his presentation today, Paul Hudson, Astra’s Executive Vice President, North America, said that the key would be focusing on one key fact: Brilinta reduced cardiovascular deaths by 21% compared to Plavix in a big clinical trial. That would mean that if everyone eligible for Brilinta got it, 100,000 lives would be saved.

But the reality is that doctors have been skeptical of that data because in the part of that trial that was run in North America, the benefit was less clear. AstraZeneca says that this may have been due to an interaction of Brilinta and aspirin and that, according to current cardiovascular guidelines, doctors should be prescribing less aspirin anyway.

Another key data point Astra presented was that blood levels of troponin, a muscle protein released by the heart during a heart attack, predict which patients get the most benefit from Brilinta. This data is not in AstraZeneca’s label, but a spokeswoman said that she believed it would be something the company can market to doctors.

A lot of what Astra will do in the short term on Brilinta will be blocking and tackling. It needs to pay bigger rebates to insurers to make sure that patients can get cheap access to the drug. (This is how discounts happen in the American insurance system: the patient pays a co-payment and the insurer pays full price for the drug, but then the drug maker gives the insurer money back to make the end cost cheaper.) It will also be doing a lot of medical marketing, involving its internal experts or paid, external doctors, to get the word out about the benefits of Brilinta.

Brilinta has other advantages (it stops acting quickly) and disadvantages (it must be given twice a day). But the other big question for expanding results is whether large clinical trials that are now ongoing will show that it works in a broader array of heart patients. Astra is starting a big trial to show Brilinta prevents strokes. These trials are risky and expensive, but there will be a big payoff if they work.

Astra has some other commercial levers to point to. It’s diabetes pill Onglyza, which is sold with Bristol-Myers Squibb, will have results in a big study of its efficacy in preventing heart disease before a similar study of Merck’s top-selling Januvia, which started first. Soriot has smart ideas about which drugs to advance into later testing. But Brilinta is going to be the biggest single indicator of whether Soriot’s new strategies are paying off.

SOURCE:

http://www.forbes.com/sites/matthewherper/2013/03/21/can-pascal-soriot-turn-around-astrazeneca-it-may-come-down-to-one-drug/

BRILINTA is an antiplatelet medication

Taking BRILINTA is a first step in the treatment your physician has chosen for you. At BRILINTA.com, you will find helpful information and useful learning tools to help you complete your course of BRILINTA therapy. Make sure you and your loved ones read through all of the sections.

What is BRILINTA?

BRILINTA is a type of prescription antiplatelet medication for people who have had a recent heart attack or severe chest pain that happened because their heart wasn’t getting enough oxygen and who are being treated with medicines or procedures to open blocked arteries in the heart. BRILINTA is used with aspirin to stop platelets from sticking together and forming a blood clot that could block blood flow to the heart and cause another, possibly fatal, heart attack. Platelets are small cells in the blood that help with normal blood clotting.

Take BRILINTA and aspirin exactly as instructed by your doctor: BRILINTA twice a day, plus one 81-mg aspirin tablet once a day. You should not take a dose of aspirin higher than 100 mg each day because it can affect how well BRILINTA works. Tell your doctor about any medicines you are taking that contain aspirin. Do not take any new medicines that contain aspirin.

Why BRILINTA?

BRILINTA used with aspirin lowers your chance of having another serious problem with your heart or blood vessels such as heart attack, stroke, or blood clots in your stent if you received one. These can be fatal. In fact, in a large clinical study BRILINTA was even better than Plavix® (clopidogrel bisulfate) tablets at lowering your chances of having another heart attack.

BRILINTA is used to lower your chance of having another heart attack or dying from a heart attack, but BRILINTA (and similar drugs) can cause bleeding that can be serious and sometimes lead to death.

Complete the
Course Program

IMPORTANT SAFETY INFORMATION ABOUT BRILINTA

BRILINTA is used to lower your chance of having another heart attack or dying from a heart attack or stroke, but BRILINTA (and similar drugs) can cause bleeding that can be serious and sometimes lead to death. Instances of serious bleeding, such as internal bleeding, may require blood transfusions or surgery. While you take BRILINTA, you may bruise and bleed more easily and be more likely to have nosebleeds. Bleeding will also take longer than usual to stop.

Call your doctor right away if you have any signs or symptoms of bleeding while taking BRILINTA, including: severe, uncontrollable bleeding; pink, red, or brown urine; vomit that is bloody or looks like coffee grounds; red or black stool; or if you cough up blood or blood clots.

Do not stop taking BRILINTA without talking to the doctor who prescribes it for you. People who are treated with a stent, and stop taking BRILINTA too soon, have a higher risk of getting a blood clot in the stent, having a heart attack, or dying. If you stop BRILINTA because of bleeding, or for other reasons, your risk of a heart attack or stroke may increase. Tell all your doctors and dentists that you are taking BRILINTA. To decrease your risk of bleeding, your doctor may instruct you to stop taking BRILINTA 5 days before you have elective surgery. Your doctor should tell you when to start taking BRILINTA again, as soon as possible after surgery.

Take BRILINTA and aspirin exactly as instructed by your doctor. You should not take a dose of aspirin higher than 100 mg daily because it can affect how well BRILINTA works. Tell your doctor if you take other medicines that contain aspirin. Do not take new medicines that contain aspirin.

Do not take BRILINTA if you are bleeding now, especially from your stomach or intestine (ulcer), have a history of bleeding in the brain, or have severe liver problems.

BRILINTA can cause serious side effects, including bleeding and shortness of breath. Call your doctor if you have new or unexpected shortness of breath or any side effect that bothers you or that does not go away. Your doctor can decide what treatment is needed.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. BRILINTA may affect the way other medicines work, and other medicines may affect how BRILINTA works.

Approved uses
BRILINTA is a prescription medicine for people who have had a recent heart attack or severe chest pain that happened because their heart wasn’t getting enough oxygen and who are being treated with medicines or procedures to open blocked arteries in the heart.

BRILINTA is used with aspirin to lower your chance of having another serious problem with your heart or blood vessels such as heart attack, stroke, or blood clots in your stent if you received one. These can be fatal.

Please read Prescribing Information, including Boxed WARNINGS.

Please read Medication Guide.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

If you are without prescription coverage and cannot afford your medication, AstraZeneca may be able to help. For more information, please visit www.AstraZeneca.com.

This product information is intended for US consumers only.

BRILINTA is a trademark of the AstraZeneca group of companies.

Plavix® is a registered trademark of sanofi-aventis.

©2012 AstraZeneca.706809-1789005 8/12

SOURCE:

http://www.brilinta.com/antiplatelet-prescription-medication.aspx#au

http://www1.astrazeneca-us.com/pi/brilinta.pdf

BRILINTA (ticagrelor)

Ticagrelor (trade name Brilinta in the US, Brilique and Possia in the EU) is a platelet aggregation inhibitor produced by AstraZeneca. The drug was approved for use in the European Union by the European Commission on December 3, 2010.[1][2] The drug was approved by the US Food and Drug Administrationon July 20, 2011.[3]

Indications

Ticagrelor is indicated for the prevention of thrombotic events (for example stroke or heart attack) in patients with acute coronary syndrome or myocardial infarction with ST elevation. The drug is combined with acetylsalicylic acid unless the latter is contraindicated.[4] Treatment of acute coronary syndrome with ticagrelor as compared with clopidogrel significantly reduces the rate of death.[5]

Contraindications

Contraindications for ticagrelor are: active pathological bleeding and a history of intracranial bleeding, as well as reduced liver function and combination with drugs that strongly influence activity of the liver enzymeCYP3A4, because the drug is metabolized via CYP3A4 and excreted via the liver.[4]

Adverse effects

The most common side effects are shortness of breath (dyspnea, 14%)[6] and various types of bleeding, such as hematoma, nosebleed, gastrointestinal, subcutaneous or dermal bleeding. Allergic skin reactions such as rash and itching have been observed in less than 1% of patients.[4]

Physical and chemical properties

Ticagrelor is a nucleoside analogue: the cyclopentane ring is similar to the sugar ribose, and the nitrogen rich aromatic ring system resembles the nucleobase purine, giving the molecule an overall similarity toadenosine. The substance has low solubility and low permeability under the Biopharmaceutics Classification System.[1]

Ticagrelor as a nucleoside analogue

The nucleoside adenosinefor comparison

Pharmacokinetics

Ticagrelor is absorbed quickly from the gut, the bioavailability being 36%, and reaches its peak concentration after about 1.5 hours. The main metabolite, AR-C124910XX, is formed quickly via CYP3A4 by de-hydroxyethylation at position 5 of the cyclopentane ring.[7] It peaks after about 2.5 hours. Both ticagrelor and AR-C124910XX are bound to plasma proteins (>99.7%), and both are pharmacologically active. Blood plasma concentrations are linearly dependent on the dose up to 1260 mg (the sevenfold daily dose). The metabolite reaches 30–40% of ticagrelor’s plasma concentrations. Drug and metabolite are mainly excreted via bile and feces.

Plasma concentrations of ticagrelor are slightly increased (12–23%) in elderly patients, women, patients of Asian ethnicity, and patients with mild hepatic impairment. They are decreased in patients that described themselves as ‘coloured’ and such with severe renal impairment. These differences are considered clinically irrelevant. In Japanese people, concentrations are 40% higher than in Caucasians, or 20% after body weight correction. The drug has not been tested in patients with severe hepatic impairment.[4]

Mechanism of action

Like the thienopyridines prasugrel, clopidogrel and ticlopidine, ticagrelor blocks adenosine diphosphate (ADP) receptors of subtype P2Y12. In contrast to the other antiplatelet drugs, ticagrelor has a binding site different from ADP, making it an allosteric antagonist, and the blockage is reversible.[8] Moreover, the drug does not need hepatic activation, which might work better for patients with genetic variants regarding the enzyme CYP2C19 (although it is not certain whether clopidogrel is significantly influenced by such variants).[9][10][11]

Comparison with clopidogrel

The PLATO trial, funded by AstraZeneca, in mid-2009 found that ticagrelor had better mortality rates than clopidogrel (9.8% vs. 11.7%, p<0.001) in treating patients with acute coronary syndrome. Patients given ticagrelor were less likely to die from vascular causes, heart attack, or stroke but had greater chances of non-lethal bleeding (16.1% vs. 14.6%, p=0.0084), higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more instances of fatal intracranial bleeding. Rates of major bleeding were not different. Discontinuation of the study drug due to adverse events occurred more frequently with ticagrelor than with clopidogrel (in 7.4% of patients vs. 6.0%, P<0.001)[5] The PLATO trial showed a statistically insignificant trend toward worse outcomes with ticagrelor versus clopidogrel among US patients in the study – who comprised 1800 of the total 18,624 patients. The HR actually reversed for the composite end point cardiovascular (death, MI, or stroke): 12.6% for patients given ticagrelor and 10.1% for patients given clopidogrel (HR = 1.27). Some believe the results could be due to differences in aspirin maintenance doses, which are higher in the United States.[12] Others state that the central adjudicating committees found an extra 45 MIs in the clopidogrel (comparator) arm but none in the ticagrelor arm, which improved the MI outcomes with ticagrelor. Without this adjudication the trials’ primary efficacy outcomes should not be significant[13]

Consistently with its reversible mode of action, ticagrelor is known to act faster and shorter than clopidogrel.[14] This means it has to be taken twice instead of once a day which is a disadvantage in respect of compliance, but its effects are more quickly reversible which can be useful before surgery or if side effects occur.[4][15]

Interactions

Inhibitors of the liver enzyme CYP3A4, such as ketoconazole and possibly grapefruit juice, increase blood plasma levels and consequently can lead to bleeding and other adverse effects. Conversely, drugs that are metabolized by CYP3A4, for example simvastatin, show increased plasma levels and more side effects if combined with ticagrelor. CYP3A4 inductors, for example rifampicin and possibly St. John’s wort, can reduce the effectiveness of ticagrelor. There is no evidence for interactions via CYP2C9.

The drug also inhibits P-glycoprotein (P-gp), leading to increased plasma levels of digoxin, ciclosporin and other P-gp substrates. Ticagrelor and AR-C124910XX levels are not significantly influenced by P-gp inhibitors.[4]

In the US a boxed warning states that use of ticagrelor with aspirin doses exceeding 100 mg/day decreases the effectiveness of the medication.[16]

References

  1. ^ a b “Assessment Report for Brilique”. European Medicines Agency. January 2011.
  2. ^ European Public Assessment Report Possia
  3. ^ “FDA approves blood-thinning drug Brilinta to treat acute coronary syndromes”. FDA. 20 July 2011.
  4. ^ a b c d e f Haberfeld, H, ed. (2010) (in German). Austria-Codex (2010/2011 ed.). Vienna: Österreichischer Apothekerverlag.
  5. ^ a b Wallentin, Lars; Becker, RC; Budaj, A; Cannon, CP; Emanuelsson, H; Held, C; Horrow, J; Husted, S et al. (August 30, 2009). “Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes”. NEJM 361 (11): 1045–57. doi:10.1056/NEJMoa0904327. PMID 19717846.
  6. ^ Brilinta: Highlights of prescribing information
  7. ^ Teng, R; Oliver, S; Hayes, MA; Butler, K (2010). “Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects”. Drug metabolism and disposition: the biological fate of chemicals 38 (9): 1514–21. doi:10.1124/dmd.110.032250. PMID 20551239.
  8. ^ Birkeland, Kade; Parra, David; Rosenstein, Robert (2010). “Antiplatelet therapy in acute coronary syndromes: focus on ticagrelor”. Journal of Blood Medicine 1: 197–219.
  9. ^ H. Spreitzer (February 4, 2008). “Neue Wirkstoffe – AZD6140” (in German). Österreichische Apothekerzeitung (3/2008): 135.
  10. ^ Owen, RT, Serradell, N, Bolos, J (2007). “AZD6140”. Drugs of the Future 32 (10): 845–853. doi:10.1358/dof.2007.032.10.1133832.
  11. ^ Tantry, Udaya S; Bliden, Kevin P (2010). “First Analysis of the Relation Between CYP2C19 Genotype and Pharmacodynamics in Patients Treated With Ticagrelor Versus Clopidogrel”. Circulation: Cardiovascular Genetics 3: 556–566. doi:10.1161/CIRCGENETICS.110.958561.
  12. ^ Bernardo Lombo, José G Díez. Ticagrelor: the evidence for its clinical potential as an oral antiplatelet treatment for the reduction of major adverse cardiac events in patients with acute coronary syndromes Core Evid. 2011; 6: 31–42. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065559/
  13. ^ Serebruany VL, Atar D. Viewpoint: Central adjudication of myocardial infarction in outcome-driven clinical trials—Common patterns in TRITON, RECORD, and PLATO? Thromb Haemost 2012; DOI: 10.1160/TH12-04-0251. http://www.theheart.org/article/1433145/print.do
  14. ^ Miller, R (24 February 2010). “Is there too much excitement for ticagrelor?”. TheHeart.org.
  15. ^ H. Spreitzer (17 January 2011). “Neue Wirkstoffe – Elinogrel” (in German). Österreichische Apothekerzeitung (2/2011): 10.
  16. ^ July 20, 2011 AstraZeneca: Ticagrelor (Brilinta) Gains FDA Approval Larry Husten cardiobrief.org/2011/07/20/astrazeneca-ticagrelor-brilinta-gains-fda-approval/

SOURCE:

 http://en.wikipedia.org/wiki/Ticagrelor

Read Full Post »

Early Surgery May Benefit Some With Heart Infection

Posted in Disease Biology, Small Molecules in Development of Therapeutic Drugs, Frontiers in Cardiology and Cardiovascular Disorders, Infectious Disease & New Antibiotic Targets, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, Valves & Tools, tagged , , , , , , , , on August 2, 2012| Leave a Comment »

Early Surgery May Benefit Some With Heart Infection

Reporter: Aviva Lev-Ari, RN

 

Early Surgery May Benefit Some With Heart Infection, but doctors say findings only apply to a certain few

June 27, 2012 

By Denise Mann
HealthDay Reporter

http://health.usnews.com/health-news/news/articles/2012/06/27/early-surgery-may-benefit-some-with-heart-infection?page=2

WEDNESDAY, June 27 (HealthDay News) — People with an advanced form of a heart infection called endocarditis may do better if they undergo early surgery than if they are treated with antibiotics initially, a new study suggests.

Infective or bacterial endocarditis occurs when bacteria settles in the heart lining or heart valve. In advanced cases, the abnormal bacterial growth, often called vegetation, can be large enough to break off and travel elsewhere in the body, such as to the brain, where it may cause a stroke. Advanced infective endocarditis can also damage the heart valve.

People with existing heart disease or heart-valve problems are most likely to develop endocarditis.

In a new study published June 28 in the New England Journal of Medicine, researchers evaluated close to 80 people, average age 47, with advanced infective endocarditis.

Of these, 37 had early surgery within 48 hours of their diagnosis, and 39 received conventional therapy with antibiotics while they were monitored to see if the infection abated. Thirty people placed in the conventional treatment group eventually had surgery.

Early surgery reduced the risk of developing an embolism (or clot) and did not increase the risk of in-hospital death, the study showed.

After six months, the rate of adverse events, including death, repeat hospitalization for congestive heart failure or a recurrence of endocarditis, was 3 percent in the early-surgery group versus 28 percent in the conventionally treated patients.

“Early surgery can be the preferred option to further improve clinical outcomes of infective endocarditis, which is associated with considerable morbidity and mortality,” said study author Dr. Duk-Hyun Kang, a cardiologist at University of Ulsan College of Medicine in Seoul, South Korea.

“If a patient with infective endocarditis has large vegetations and severe valve disease, we would advise them to request early referral to medical centers with adequate experience and resources for early surgery,” Kang said.

Surgery for infective endocarditis aims to remove all infected tissue, repair the heart tissue and repair or replace the affected valve.

Others experts said only certain patients would warrant early surgery.

The new study “showed that patients with the combination of large vegetations and valve dysfunction, even if they are stable and not in heart failure, have a high risk of suffering serious embolic events or to progress to heart failure with need for emergency surgery and that early surgery prevented these complications,” said Dr. Gosta Pettersson, co-author of an accompanying journal editorial and vice chair of thoracic and cardiovascular surgery at the Cleveland Clinic in Ohio.

Surgery does have its share of risks, however. “Historically, surgery for infective endocarditis was high-risk surgery, and the risk of recurrent infection on the replacement valve was also high,” he said.

“Today, several publications have demonstrated that the added risk of operating on a patient with active infection has been more or less neutralized,” Pettersson added.

Surgeons have become adept at removing all infected tissue and foreign material and determining how best to reconstruct the heart, he explained. “Taking care of this patient is a team work with close collaboration between infectious disease specialists, cardiologists and cardiac surgeons,” he said. Importantly, he noted, “surgery is a complement to antibiotics not an alternative.”

Not everyone with infective endocarditis should have surgery, Pettersson said. For example, the stable patient with small vegetations, preserved valve function and growth of bacteria sensitive to antibiotics does not need surgery. Severely ill patients who are unlikely to survive an operation or those who have irreversible brain damage from embolism would not be surgical candidates either, he pointed out.

Dr. Stephen Green, chief of cardiology at North Shore University Hospital in Manhasset, N.Y., said that the new findings only apply to a select few. “Patients in the study had very large vegetation and severe valve pathology,” Green said. “These tend to be the worst of the worst.”

Most people with infective endocarditis are treated with antibiotics. “We reserve surgery for people whose infections don’t resolve, have fever or bacteria in the bloodstream or whose valves get destroyed,” Green noted.

“Many people with milder forms can be treated with antibiotics and monitored long term to see if they need surgery,” he added. This study suggests that “if you get a really bad clump of stuff on a valve, even if it’s antibiotic-sensitive, maybe we should go to surgery earlier.”

More information

Learn more about infective endocarditis at the American Heart Association.

Copyright © 2012 HealthDay. All rights reserved.

Read Full Post »

Treatment of Refractory Hypertension via Percutaneous Renal Denervation

Posted in Cardiac & Vascular Repair Tools Subsegment, Ecosystems & Industrial Concentration in the Medical Device Sector, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, HTN, Massachusetts Niche Suppliers and National Leaders, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Pharmacotherapy of Cardiovascular Disease, Renal Denervation, tagged , , , , , , , , , , , , , , , , on June 13, 2012| 15 Comments »

Treatment of Refractory Hypertension via Percutaneous Renal Denervation 

Curator: Aviva Lev-Ari, PhD, RN

UPDATED  8/5/2013

VIEW VIDEO – Editorial the Heart.org

Renal denervation: Clinical lessons from around the world

Renal Denervation treatment represents a medical subfield, it has its roots in surgical sympathectomy techniques dating back to the 1930s. This radical approach to blood pressure control, which did not specifically target renal nerves, was ultimately abandoned due to associated perioperative complications. However, experience in renal transplantation, a procedure in which the renal nerves are selectively severed, suggests that the denervated kidney can maintain volume and electrolyte homeostasis.

http://ajpregu.physiology.org/content/298/2/R245.full

http://www.ncbi.nlm.nih.gov/pubmed/3326559?dopt=Abstract

Potential effects of renal denervation are on improved glucose control, sleep apnea, and treatment of heart failure syndromes and renal dysfunction – all consequences of sustained hypersympathetic activity.

Based on these observations, the specific targeting of renal nerves as a major operative in the pathophysiology of hypertension and other conditions associated with increased sympathetic activity (renal dysfunction and heart failure) appears to be an attractive therapeutic approach.

http://bmctoday.net/evtoday/2012/02/article.asp?f=renal-artery-denervation-a-brave-new-frontier

A new therapeutic paradigm of percutaneous renal artery denervation using the application of radiofrequency (RF) energy (Symplicity renal denervation system [Ardian, acquired by Medtronic, Inc., Minneapolis, MN]) has recently been demonstrated to be safe, effective, and durable in significantly reducing systolic blood pressure in patients with resistant hypertension.

This new technology represents the first time that physicians have been able to target renal nerves specifically via a catheter-based intervention. This endovascular approach opens the door to better understanding the relationship between sympathetic hyperactivity and hypertension.

Current therapeutic strategies center on lifestyle changes and pharmacologic interventions; however, the rates of blood pressure control and therapeutic efforts to reduce the rate of progression of hypertensive end-organ damage (resulting in myocardial infarction, stroke, and renal dysfunction) remain a neglected priority.

http://rd.springer.com/article/10.1007/s11906-010-0119-1

Renal denervation is used to treat uncontrolled hypertension, or high blood pressure, by the ablation of the nerves that line the renal arteries using a catheter. The Cleveland Clinic called renal denervation the No. 1 healthcare innovation of 2012. More than 12 million patients worldwide whose blood pressure remains uncontrolled despite taking three or more anti-hypertensive medications representing a global market opportunity for renal denervation that could ultimately grow to $30 billion. The Millennium Research Group estimates that the hypertension-treating devices could generate $4.4 billion per year, Bloomberg reported. That number could swell if the FDA indicates the systems for simple hypertension and not just the drug-resistant sort. As Bloomberg notes, a boom in hypertension devices would be a welcome development for the device industry, which has struggled over the past four years with recalls, litigation and regulatory woes, leading to a 7% decline in Standard & Poor’s Healthcare Equipment Index.

“At least 23 companies, mainly smaller, private companies are developing products,” Wang said, based on information she gathered at the American College of Cardiology Conference in Chicago in March.

http://medcitynews.com/2012/04/medtronic-aside-a-whole-host-of-firms-chasing-hypertension-market/

http://www.fiercemedicaldevices.com/story/bloomberg-hypertension-devices-could-pay-big-us/2012-05-25?utm_medium=nl&utm_source=internal

According to the American Heart Association, a 5 mm Hg (millimeters of mercury) reduction in systolic blood pressure results in a 14 percent decrease in stroke, a 9 percent decrease in heart disease, and a 7 percent decrease in overall mortality. Renal denervation has shown in clinical studies to be safe, durable and effective in reducing systolic blood pressure by as much as 20 percent.

Numerous analysts suggest that there are more than 12 million patients worldwide whose blood pressure remains uncontrolled, despite taking three or more anti-hypertensive medications. This represents a global market opportunity for renal denervation approaching $30 billion.

Procedure Benefits

Hypertension, though often asymptomatic, is the number one risk factor for premature death worldwide.1 Renal Denervation (RDN) treatment aims to address this condition at its source to provide a substantial and durable reduction in blood pressure. After the procedure, people can often return to their normal activities quickly. The benefit is often achieved after several weeks to months.

Benefits and New Indications for Usage of Intravascular Stimulation/Ablation of Autonomics

1. Reduction in Heart Rate and Heart Rate Variability

Dr. Scherlag experiments noted changes in heart rate which have also been reported in SYMPLICITY HTN-1 and SYMPLICITY HTN-2 (8-9).  The SYMPLICITY HTN-2 study demonstrated profound bradycardia in 13% of patients that was treated with atropine.

The intra-procedure effect on heart rate during renal artery denervation documented in the  SYMPLICITY trials is also manifest long term by measuring heart rate variability (10). Indeed, cardiac effects would be expected with autonomic modulation.  Besides the two example above showing that cardiac sympathetic denervation effects heart rate, there are many more that are just beginning to be reported in the literature.

These articles shows the effects of renal denervation on heart rate.

http://www.ncbi.nlm.nih.gov/pubmed/1735574
http://www.ncbi.nlm.nih.gov/pubmed/8777835

A Cleveland Clinic review article states: “Additionally, the resting heart rate was lower and heart rate recovery after exercise improved after the procedure, particularly in patients without diabetes.”
http://www.ccjm.org/content/79/7/501.full

2. Renal Sympathetic Denervation lowers Atrial Fibrillation

This article discusses the effect of renal sympathetic denervation on atrial fibrillation.

http://www.ncbi.nlm.nih.gov/pubmed/22585944

3. Regression of Left Ventricular Hypertrophy, Increase in Ejection Fraction (EF) and improved Diastolic Dysfunction

“Brandt reported regression of left ventricular hypertrophy and significantly improved cardiac functional parameters, including increase in ejection fraction and improved diastolic dysfunction, in a study of 46 patients who underwent renal denervation. This findings suggests a potential beneficial effect on cardiac remodeling.” (Brandt MC, Mahfoud F, Reda S, et al. Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. J Am Coll Cardiol 2012; 59:901–909)

4. Reduction in Ventricular Tachyarrhythmias (VT)

“Ukena reported reduction in ventricular tachyarrhythmias in two patients with congestive heart failure who had therapy-resistant electrical storm.” (Ukena C, Bauer A, Mahfoud F, et al. Renal sympathetic denervation for treatment of electrical storm: first-inman experience. Clin Res Cardiol 2012; 101:63–67)

5. Intravascular Stimulation of Autonomics Effects on Heart Failure

The most recent data from Europe shows the following effects on heart failure:

http://www.eurekalert.org/pub_releases/2012-08/esoc-rdg082712.php
http://www.theheart.org/article/1364267.do

Dr. Scherlag, writes, [N]early ten examples of the effects of “CARDIAC SYMPATHETIC DENERVATION” and what are the effects on the kidney?

No change in GFR.  No change in creatinine.

http://pharmaceuticalintelligence.com/2012/09/02/imbalance-of-autonomic-tone-the-promise-of-intravascular-stimulation-of-autonomics/

Procedure Risks

Although major complications are uncommon, RDN treatment carries many of the same risks as an angioplasty procedure for the treatment of artery disease. The catheter insertion site could become infected, become bruised or bleed heavily. Other possible complications include heart attack, stroke, kidney damage or malfunction, heart rhythm disturbances, arterial damage, hypotension, sudden cardiac death, burns and pain. Imaging agents, pain medications and anti-spasm agents are commonly used during the procedure and carry known risks.

1. Mathers, C., et al. World Health Organization; 2009

http://www.ardian.com/ous/patients/benefits-risks.shtml

Medical Debate on the Procedure – The candidates are hypertensive patients receiving blood-pressure-lowering medication that are truly “resistant.”

The Symplicity system (Medtronic) is the far-and-away front runner, having demonstrated average office-based BP drops of 32/12 mm Hg at six months in the SYMPLICITY HTN 2 trial, as reported by heartwire, with 84% of patients having had a >10-mm-Hg drop in systolic blood pressure from baseline.

Upwards of 20 other companies, according to Dr Ron Waksman (Washington Hospital, DC), are busy developing competing systems, some of which were featured in a EuroPCR session devoted to emerging technologies in May 2012 in Paris.

Leading this pack is St Jude’s EnligHTN system, which received CE Mark on the opening day of the meeting. Dr Stephen Worthley (Royal Adelaide Hospital, Australia) presented 30-day results in 47 resistant-hypertension patients treated with the multielectrode, RF-ablation-based system. Mean office BP changes at one month in EnligHTN 1 were -28 systolic and -10 diastolic (p<0.0001 from baseline), with 78% of patients having systolic BP drops of >10 mm Hg.

https://www.massdevice.com/news/europcr-st-judes-enlightn-lowers-blood-pressure-faster-rival-systems

In terms of safety, no serious complications were seen in the renal artery or at the access site in the EnligHTN study; minor procedure-related events included four hematomas, three vasovagal responses to sheath removal, and two postprocedure transient bradycardias.

Other devices featured in the session included a second RF-energy system and two ultrasound systems, see below technology description by supplier.

The risk of cardiovascular death doubles with every 20 point increase in systolic blood pressure, so an average blood pressure reduction of 28 points is quite significant and demonstrates just how effective the technology is. Principal investigator Prof. Stephen Worthley said in prepared remarks. “From other clinical trials studying the impact of renal denervation we have learned that blood pressure continues to be reduced over time, so I would not be surprised to see this trend continue and see an even greater benefit for patients.” St. Jude’s study included 47 patients with high blood pressure that wasn’t managed with drug therapy. Participants had an average of 176/96 mmHg baseline blood pressure, despite taking multiple medications, before the denervation procedure and an average of 148/87 mmHg after. More than 40% had systolic rates below 140 mmHg.

http://investors.sjm.com/phoenix.zhtml?c=73836&p=irol-newsArticle&ID=1695802

Interventionalists who spoke with heartwire were unvaryingly excited about the potential of renal denervation, with some caveats.

“You need enthusiasm to develop new things, and in hypertension we haven’t seen an innovation in decades,” Dr Thomas Lüscher (University Hospital Zürich, Switzerland) told heartwire. “So just the possibility that you would be able to have a persistent treatment effect by a procedure that helps severe hypertension patients and maybe in the future even the option to cure hypertension is very exciting indeed. But I agree it’s a dream at this point. I think we need the SYMPLICITY HTN 3 trial, which hopefully will confirm what the other studies have shown.”

Now enrolling at as many as 90 US centers, SYMPLICITY HTN 3, Lüscher pointed out, has design characteristics addressing two concerns with the earlier trials, namely a sham procedure for the control group and ambulatory blood-pressure monitoring in all patients.

During the same emerging-technologies session, Lüscher explored the albeit-scant data supporting a role for renal denervation in other conditions: everything from metabolic syndrome and obstructive sleep apnea to heart failure, atrial fibrillation, and polycystic-ovary syndrome.

But his counterpoint, Dr Jean Renkin (UCL St Luc University Hospital, Brussels, Belgium), was skeptical, pointing to the myriad unanswered questions with the technology.

“Currently, reasonably solid data are available only for patients with hypertension resistant to pharmacotherapy, which cannot necessarily be extrapolated to other forms of hypertension or conditions referred to [by Dr Lüscher]. However, at this point in time, no clouds have appeared in the sky, so let us dream on.”

Dr Renkin had one staggering number for the audience to consider: of 5000 patients who have undergone renal denervation, only 250 were actually treated as part of clinical studies. While no device has US approval, five denervation systems already hold CE Mark in Europe and are being used with increasing frequency.

Treating the Truly Medication Treatment “Resistant”

For a comprehensive presentation of Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes, refer to

http://pharmaceuticalintelligence.com/2012/05/29/445/

Another talking point is the proportion of patients who are truly “resistant.” The number agreed on by Lüscher, Waksman, and session comoderator Dr Robert Whitbourn (St Vincent’s Hospital, Fitzroy, Australia) was that just 3% of all hypertensive patients receiving blood-pressure-lowering medication are truly “resistant.” Numbers as high as 30% have been suggested in other reports, he noted.

“Interestingly, when we’ve been involved in various trials, every cardiologist says they have hundreds of these patients, but when we actually go to get them, no one actually has any,” Whitbourn quipped. “I think it should be a sobering thought—the numbers are actually quite small.”

Dr William Wijns (Cardiovascular Center Aalst, Belgium), also speaking with heartwire, agreed that the subset was “small” but argued it was “still big numbers, millions of people,” and “a massive unmet need.”

Waksman, insisting he was “excited” by what he called “robust reductions in blood pressure,” nevertheless urged eager interventionalists to work with hypertension experts and resist the urge “to jump on patients before we truly verify that they are resistant to medical treatment.”

In the vast majority of people even for whom renal denervation is appropriate, it “won’t be a cure,” Waksman said. “Most of these patients will have to continue on medical treatment—this is not replacing medical treatment, it is just getting [patients] more in control.”

http://www.theheart.org/article/1402321/print.do

The Global Supplier Ecosystem for Renal Denervation Systems

US Campbell, CA Kona Medical is attempting to address these limitations. The system delivers energy from outside the patient to the renal nerves. Ultimately, the procedure will be a “no puncture,” noninvasive technique, compatible with technologies that will allow for temperature and lesion mapping. A noninvasive procedure will allow titration of the therapy— that is, the application of patient-specific dose fractions while monitoring therapeutic effect in between fractions. The basis of the technology is focused ultrasound, not high intensity (HIFU) as one might see and expect in the treatment of tumors, but low-intensity focused ultrasound (LIFU). The biologic underpinnings of this treatment are described in past literature for treating nerves using ultrasound. Kona noninvasive system. The system is depicted in a custom chair; another version of the system is compatible with a standard fluoroscopy or MRI table. Both ultrasound (through elastography and the evolution of temperature mapping and MRI) allow further imaging and analysis of the treatment area. The dose distribution surrounding the artery is that of an annular ring around the wall of the artery. Kona has shown in animal studies that a heat/vibratory cloud at one plane along the artery is highly effective at long-term inhibition of renal nerves with no visible effect on any portion of the artery at any time point.

US, Ronkonkoma, NY & Germany – Paradise  by ReCor Medical 6-F compatible catheter with a cylindrical transducer that emits ultrasound energy circumferentially, allowing for a more efficient renal denervation procedure First-in-human (15 patients at 3 months) BP drop, mm Hg -32/-16 at 3 mo. The ultrasound transducer lies within a low-pressure balloon that allows for self-centering of the transducer and gentle contact with the artery wall for uniform circumferential denervation. This means that nerves below the surface of the artery wall are damaged in 360° with a single emission. The balloon also enables cooled fluid to circulate during the energy delivery process, thereby cooling the endothelial wall and protecting it from any excessive heating that could be caused by other energy sources or designs. Preliminary F-I-M clinical data for PARADISE were reported previously at the “TRenD 2012” transcatheter renal denervation scientific meeting by cardiologist Thomas A. Mabin, M.D., Vergelegen Medi-Clinic, South Africa. The updated PARADISE data show that systolic blood pressure was reduced by a statistically significant average of 36 mm Hg in 8 patients at 90-days follow-up. The scientific literature demonstrates that only a 5 mm Hg reduction in BP results in a 14% decrease in stroke, a 9% decrease in heart disease, and a 7% decrease in mortality.

US, San Leandro, CA The Mercator Bullfrog by Mercator MedSystems, Inc. is a catheter-guided system designed to inject therapeutic agents directly, nonsystemically, and safely through blood vessel walls into adventitial tissues and has received US Food and Drug Administration 510(k) clearance. The Bullfrog catheter is tipped with a balloon-sheathed microneedle and is guided and inflated in a manner similar to an angioplasty catheter but with far lower expansion pressures (2 atm vs 6–20 atm) in vessels of 3 to 6 mm in diameter. It is compatible with 0.014-inch guidewires and 6-F introducer sheaths. When the desired injection site is reached, the balloon is inflated with saline and radiopaque contrast, securing the system for injection and sliding the microneedle through the vessel wall. Nonclinical studies have shown that the Bullfrog catheter is able to deliver up to 5 mL per injection into the renal artery adventitia with no apparent safety concerns. Guanethidine Ismelin) is delivered to the renal artery adventitia to accomplish sympathetic denervation. Given locally, guanethidine is known to induce an autonomic denervation directly and through an immune-mediated pathway. Mercator’s preclinical experiments have shown that guanethidine, injected at appropriate concentrations into the adventitial space around renal arteries, selectively ablates the nerves in the adventitia around the renal artery after a single, 20-minute procedure

J Neurosci. 1983;3:714-724

US – Laguna Hills, CA – V2 Radiofrequency Baloon by Vessix Vascular, Inc. Bipolar RF balloon catheter REDUCE-HTN pilot (10 patients)

BP drop, mm Hg -30/-11 at 1 mo V 2 catheter, a patented noncompliant balloon catheter with RF electrodes and thermistors mounted on the exterior of the balloon, and the proprietary V 2 bipolar RF generator. Once inserted into the renal artery, a 30-second inflation/treatment per renal artery delivers simultaneous RF therapy with independent temperature control to all electrode pairs. V 2 catheter is available in balloon diameters ranging from 4 to 7 mm, with a balloon length of 25 mm. Larger-diameter balloons have eight electrode pairs, and smaller-diameter balloons have four to six electrode pairs made of solid gold, which are biocompatible and facilitate good electrode contact with the renal arterial wall. In addition, the electrodes are radiopaque, allowing the V 2 catheter to be easily visualized under fluoroscopy. Beginning in the first quarter of 2012, the V 2 renal denervation system will be utilized in the company’s first international, multicenter clinical study: REDUCEHTN.

Israel, Tel Aviv – Tivus by Cardiosonic  A6-F transducer-tipped catheter, ultrasound energy (Animal data only) The solution for renal denervation is a high-intensity, nonfocused ultrasonic (US) catheter system named TIVUS (Therapeutic IntraVascular UltraSound) (Figure 3). By applying ultrasonic energy, the TIVUS technology enables remote, localized, controlled, and repeatable thermal modulation of the renal vessel wall tissue, resulting in safe renal nerve ablation. The remote thermal effect is located in the adventitia and perivascular region, with no thermal damage to the endothelium and media, therefore, preventing the development of vessel injury processes. Swine kidney tissue NE concentrations at 30- and 90-day follow-up have demonstrated successful renal denervation as witnessed by a 50% or more decline in tissue NE. Localized tissue thermal modulation/ablation, without damage to the blood vessel wall.

US, MN – SYMPLICITY HTN 2 by Medtronic   average office-based BP drops of BP drop, mm Hg 32/12 mm Hg at six months in the SYMPLICITY HTN 2 trial, as reported by heartwire, with 84% of patients having had a >10-mm-Hg drop in systolic blood pressure from baseline. 14 points in 30 days and 27 points after 1 year. Available in Europe. Medtronic is the furthest ahead in its development process, predicting it will get Symplicity on the American market by 2015. catheter in the renal artery near each kidney to deliver radiofrequency energy to ablate the nerves. A single electrode in contrast to St. Jude’s mutli-electrode approach, is already on the road to FDA review with clinical trials approved last summer in the U.S. Symplicity system has been safely used in nearly 5,000 patients since commercialization

US, MN – EnligHTN 1 by  St Jude radiofrequency (RF) energy to create lesions (tiny scars) along the renal sympathetic nerves Mean office BP changes at one month in BP drop, mm Hg 28 systolic and -10 diastolic after 1 month (p<0.0001 from baseline), with 78% of patients having systolic BP drops of >10 mm Hg. St. Jude Medical’s (St. Paul, MN) announcement in late 2011 of the first patient to be enrolled in their first-in-man ARSENAL trial 15 at the University of Adelaide

Ireland, Dublin – OneShot™ by Covidien acquisition of Maya Medical, Saratoga, CA New Irrigated RF Balloon Catheter secure first human use for the device in the third quarter of this year, followed by a CE mark for the drug-resistant hypertension treatment in 2013. Presumably, a filing with the FDA would follow that. the OneShot renal denervation system, was born out of the company’s extensive expertise in radiofrequency (RF) ablation and percutaneous coronary interventions (PCI), drawing upon the benefits and best practice standards of each distinct yet complementary clinical discipline. The result is a unique product platform that could further accelerate the paradigm shift in the management of resistant hypertension. consistent with Maya’s balloon-based approach is the ability to deliver predictable apposition of the RF electrode to the vessel wall for more controlled targeted delivery of the RF energy. By offering a more reliable single-treatment approach coupled with enhanced ease of use and reduced procedure times, Maya Medical believes its OneShot renal denervation system has the potential to significantly expand clinical adoption

http://bmctoday.net/evtoday/2012/02/article.asp?f=renal-artery-denervation-a-brave-new-frontier

US, Natick, MA Boston Scientific lags behind in the race to cash in on hypertension-treating devices, incoming CEO Michael Mahoney said at a Monday conference that it has a plan for its RDN renal denervation system. As MassDevice reports, Mahoney said Boston Sci expects to secure first human use for the device in the third quarter of this year, followed by a CE mark for the drug-resistant hypertension treatment in 2013.

St Jude’s EnligHTN system

Said Frank Callaghan, president of the St. Jude Medical Cardiovascular Division “This launch is important because it represents a significant growth opportunity and exemplifies our commitment to advancing the practice of medicine. We’ve applied the decades of insight we’ve gained from developing successful ablation technologies that treat cardiac arrhythmias to establish an innovative solution for hypertension.” With the unique basket design, each placement of the ablation catheter allows a consistent and predictable pattern of four ablations in 90-second intervals. Compared to single electrode ablations, the multi-electrode EnligHTN system has the potential to improve consistency and procedural reliability, save time as well as result in workflow and cost efficiencies. Additionally, the minimal catheter repositioning may result in a reduction of contrast and fluoroscopic (x-ray) exposure. The technology includes a guiding catheter, ablation catheter and ablation generator. The generator uses a proprietary, temperature-controlled algorithm to deliver effective therapy.

http://investors.sjm.com/phoenix.zhtml?c=73836&p=irol-newsArticle&ID=1695802

http://medgadget.com/2012/05/st-jude-medical-launches-enlightn-renal-denervation-system.html

St Jude’s EnligHTN system – view video

http://www.sjmprofessional.com/Products/Intl/Renal-Ablation-Therapy/enlightn-renal-denervation-system.aspx

Covidien

Unveiled a Novel Renal Denervation System OneShot™ at EuroPCR congress in Paris on 5/16/2012. “Live” Cases with New Irrigated RF Balloon Catheter for Treatment of Medication-resistant Hypertension and poor outcomes of pharmacological agents. The OneShot system is an irrigated, radiofrequency (RF) based balloon catheter used to ablate the renal sympathetic nerves located in the outer wall of the renal arteries. The OneShot technology received CE mark clearance in February 2012.

The OneShot system was featured in “live” cases at the Covidien-sponsored “Tools & Techniques (TNT) Interventions” presentation and panel session for hypertension and renal denervation at the EuroPCR congress. Professor Dirk Scheinert performed two cases at Park Hospital in Leipzig, Germany, that were transmitted live at the Palais des Congrès de Paris. In addition, John Ormiston, MD, Medical Director for Mercy Angiography and President of the Asia-Pacific Society of Interventional Cardiology in New Zealand, presented first-in-human results of cases performed with the OneShot system in New Zealand. The OneShot system and Covidien’s other endovascular solutions was on display at the EuroPCR meeting.

Additional faculty in the TNT session is a distinguished group of speakers including:

Professor Karl-Heinz Kuck, MD, F.A.C.C. – Director, Cardiology Department
Allgemeines Krankenhaus St. Georg – Hamburg, Germany

Dr. Stephen R. Ramee, FACC, FSCAI
Ochsner Medical Center – New Orleans, Louisiana

Dr. John Ormiston, MBChB, FRACP – Medical Director
Mercy Hospital Angiography Unit – Auckland, New Zealand

Professor Marc Sapoval, MD, PhD – Department Head
Cardiovascular/Interventional Radiology – Hospital Pompidou University – Paris, France

Dr. Renu Virmani – Medical Director
CVPath Institute – Gaithersburg, Maryland

Covidien discloses that it purchased Maya Medical for $60 million in cash on April 20. If Maya Medical meets certain regulatory and sales milestones, it will receive up to an additional $170 million. Covidien notes that Maya Medical’s OneShot system received the CE Mark in February.

MedCity News was the first to report Covidien’s interest in Maya Medical on 5/8/2012.

In a note to investors Monday, analyst Bob Hopkins of Bank of America said that renal denervation “has the potential to be one of the largest new markets in medtech over the next 2-4 years and for [Covidien] this looks like another small deal with big potential.”

http://medcitynews.com/2012/05/covidien-discloses-60m-purchase-of-hypertension-treatment-firm/?edition=medical-devices

Clinical Trial for RAPID is ongoing

 Rapid Renal Sympathetic Denervation for Resistant Hypertension (RAPID)

This study is currently recruiting participants.

Verified June 2012 by Maya Medical

First Received on January 25, 2012.   Last Updated on June 4, 2012   History of Changes

Sponsor: Covidien (Maya Medical)
Collaborator: Meditrial Europe LTD
Information provided by (Responsible Party): Maya Medical
ClinicalTrials.gov Identifier: NCT01520506

  Purpose

Maya Medical OneShot™ Ablation System use is to deliver low-level radio frequency (RF) energy through the wall of the renal artery to denervate the human kidney.

Condition Intervention Phase
Hypertension, Resistant to Conventional Therapy Device: Maya Medical OneShot Phase 2
Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy StudyIntervention Model: Single Group AssignmentMasking: Open LabelPrimary Purpose: Treatment
Official Title: Rapid Renal Sympathetic Denervation for Resistant Hypertension Using the Maya Medical OneShot™ Ablation System

http://www.clinicaltrials.gov/ct2/results?term=Renal+Denervation&pg=2&show_flds=Y

Covidien into direct competition with Medtronic, whose Symplicity renal denervation system is approved in Europe. Currently, the system is being tested in the U.S. St. Jude Medical, Medtronic’s in-state rival, is also developing a therapy and that is expected to have a limited European market launch before the end of the year. But it is not only the larger players that Covidien will have to play against in Europe. A whole host of companies is developing products there, including ReCor Medical.

http://www.canada.com/entertainment/ReCor+Medical+discloses+data+from+clinical+study+PARADISE+ultrasound/6430884/story.html

Medtronic

Medical device giant Medtronic (NYSE: MDT), November 23, 2010 said it has agreed to pay $800 million upfront, plus commercial milestone payments through 2015, to acquire Mountain View, CA-based Ardian. Medtronic had previously built up an 11 percent ownership stake in Ardian, when it invested with its venture backers, which include Morgenthaler Ventures, Advanced Technology Ventures, Split Rock Partners, and Emergent Medical Partners. Ardian’s windfall comes about one week after it presented some eye-opening clinical trial results in The Lancet, and at the American Heart Association’s scientific meeting.

http://www.xconomy.com/san-francisco/2010/11/23/medtronic-buys-ardian-for-800m-upfront-grabs-novel-treatment-for-high-blood-pressure/

Clinical Trial for SYMPLICITY is ongoing.

Renal Denervation in Patients With Uncontrolled Hypertension (SYMPLICITY HTN-3)

This study is currently recruiting participants.

Verified June 2012 by Medtronic Vascular

First Received on August 15, 2011.   Last Updated on June 11, 2012   History of Changes

Sponsor: Medtronic Vascular
Information provided by (Responsible Party): Medtronic Vascular
ClinicalTrials.gov Identifier: NCT01418261

  Purpose

The Symplicity HTN-3 study is a, multi-center, prospective, single-blind, randomized, controlled study of the safety and effectiveness of renal denervation in subjects with uncontrolled hypertension. Bilateral renal denervation will be performed using the Symplicity Catheter – a percutaneous system that delivers radiofrequency (RF)energy through the luminal surface of the renal artery.

Condition Intervention Phase
Uncontrolled Hypertension Device: Renal denervation (Symplicity Catheter System) Phase 3
Study Type: Interventional
Study Design: Allocation: RandomizedEndpoint Classification: Safety/Efficacy StudyIntervention Model: Parallel AssignmentMasking: Single Blind (Subject)Primary Purpose: Treatment

http://clinicaltrials.gov/ct2/show/NCT01418261

 The Symplicity™ Renal Denervation System has two main components:

The elements are designed to work together as an integrated system to ensure consistent performance:

Symplicity™ Catheter – Low profile, endovascular energy delivery catheter

Symplicity™ Generator – Automated, portable RF generator

The Symplicity Renal Denervation System uses controlled, low-power radiofrequency (RF) energy to deactivate the renal nerves, thereby selectively reducing both the pathologic central sympathetic drive to the kidney and the renal contribution to central sympathetic hyperactivity. The outcome, we hope, will be a significant and sustained reduction in both blood pressure and the level of systemically damaging neurohormones. Since the endovascular procedure does not involve an implant, patients recover quickly and can soon return to their daily living. The device may usher in a new era in the treatment of hypertension, hopefully allowing a one-time procedure to offer patients a long-lasting benefit.

Medtronic Procedure – view video

http://www.ardian.com/ous/medical-professionals/procedure.shtml

Conclusions

The entire industry subsegment is awaiting the results of SYMPLICITY HTN-3. Forecasts of market share by supplier will be predicated on this Clinical Trial completion.

Shutting down overactive nerves around the kidneys as a strategy for fighting resistant hypertension is “one of the most exciting growth markets in medical devices,” Sean Salmon, vice president and general manager of Medtronic’s coronary and peripheral business, said in a statement.

I had a piece in these pages last week about what kind of difference the Ardian treatment was making. The most recent Ardian study showed the new treatment, in combination with standard drugs, was able to bring average blood pressure scores down from 178 over 97 to 146 over 85 after six months of follow-up, while those who just got standard treatments were essentially unchanged. The results were “a big achievement,” according to Murray Esler, the study’s principal investigator.

http://www.xconomy.com/san-francisco/2010/11/23/medtronic-buys-ardian-for-800m-upfront-grabs-novel-treatment-for-high-blood-pressure/

Resources

REFERENCES for Dr. Scherlag’s 1999 Patent and pioneering work on Intravascular Stimulation/Ablation of Autonomics

1. Schauerte P, Scherlag BJ, Scherlag MA, Goli S, Jackman WM, Lazzara R. Transvenous parasympathetic cardiac nerve stimulation: an approach for stable sinus rate control. J Electrophysiol. 1999 Nov;10(11):1517-24.

2. Schauerte P, Scherlag BJ, Scherlag MA, Goli S, Jackman WM, Lazzara R. Ventricular rate control during atrial fibrillation by cardiac parasympathetic nerve stimulation: a transvenous approach. J Am Coll Cardiol. 1999 Dec;34(7):2043-50.

3. Schauerte P, Scherlag BJ, Pitha J, Scherlag MA, Reynolds D, Lazzara R, Jackman WM. Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation. Circulation. 2000 Nov 28;102(22):2774-80.

4. Scherlag MA, Scherlag BJ, Yamanashi W, Schauerte P, Goli S, Jackman WM, Reynolds D, Lazzara R. Endovascular neural stimulation via a novel basket electrode catheter: comparison of electrode configurations. J Interv Card Electrophysiol. 2000 Apr;4(1):219-24.

5. Scherlag BJ, Yamanashi WS, Schauerte P, Scherlag M, Sun YX, Hou Y, Jackman WM, Lazzara R. Endovascular stimulation within the left pulmonary artery to induce slowing of heart rate and paroxysmal atrial fibrillation. Cardiovasc Res. 2002 May; 54(2):470-5.

6. Hasdemir C, Scherlag BJ, Yamanashi WS, Lazzara R, Jackman WM. Endovascular stimulation of autonomic neural elements in the superior vena cava using a flexible loop catheter. Jpn Heart J. 2003 May;44(3):417-27.

7. Webster W Jr, Scherlag BJ, Scherlag MA, Schauerte P. Method and apparatus for   transvascular treatment of tachycardia and fibrillation. US Patent 6,292,695. Filed June 17, 1999.

8. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham WT, Esler M. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373(9671):1275-1281.

9. Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376:1903-1909.

10. Frank Himmel MD, Joachim Weil MD, Michael Reppel MD, Kai Mortensen MD, Klaas Franzen, Leidinger Ansgar MD, Heribert Schunkert MD, Frank Bode MD.  Improved Heart Rate Dynamics in Patients Undergoing Percutaneous Renal Denervation. Letter to the Editor. JCH. 31 MAY 2012.1751-7176.

Sympathetic Hyperactivity & Hypertension

For more information on hypertension, please visit the medical professional hypertension portal at TheHeart.org .

Siddiqi L, Joles JA, Grassi G, Blankestijn PJ. Is kidney ischemia the central mechanism in parallel activation of the renin and sympathetic system? J Hypertens. 2009 Jul;27(7):1341-9.

Augustyniak RA, Tuncel M, Zhang W, Toto RD, Victor RG. Sympathetic overactivity as a cause of hypertension in chronic renal failure. J Hypertens. 2002;20(1):3-9.

DiBona GF. Sympathetic nervous system and the kidney in hypertension. Curr Opin Nephrol Hypertens. 2002;11(2):197-200.

Mancia G, Grassi G, Giannattasio C, Seravalle G. Sympathetic activation in the pathogenesis of hypertension and progression of organ damage. Hypertension. 1999;34(4 Pt 2):724-728.

References in Scientific Journals about Renal Denervation Treatment

Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376:1903-1909.

Symplicity HTN-1 Investigators. Catheter-Based Renal Sympathetic Denervation for Resistant Hypertension – Durability of Blood Pressure Reduction Out to 24 Months. Hypertension. Volume 57, Number 5, May 2011.

Rippy, M. et al. Catheter-Based Renal Sympathetic Denervation: Chronic Preclinical Evidence for Renal Artery Safety. Clin Res Cardiol. 2011 Dec; 100(12): Pages 1095-1101.

Mahfoud, F. et al. Effect of Renal Sympathetic Denervation on Glucose Metabolism in Patients With Resistant Hypertension. Circulation. Volume 123, No. 18, May 10, 2011. Pages 1940-1946.

Witkowski A., et al. Effects of Renal Sympathetic Denervation on Blood Pressure, Sleep Apnea Course, and Glycemic Control in Patients with Resistant Hypertension and Sleep Apnea. Hypertension. Volume 58, Number 4, October 2011. Pages 559-565.

Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham WT, Esler M. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373(9671):1275-1281.

Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler MD. Renal Sympathetic-Nerve Ablation for Uncontrolled Hypertension. N Engl J Med. 2009;361(9):932-934.

Schlaich MP, Sobotka PA, Krum H, Whitbourn R, Walton A, Esler MD. Renal Denervation as a Therapeutic Approach for Hypertension. Novel Implications for an Old Concept. Hypertension. 2009;54(6):1195-1201.

Esler M. The 2009 Carl Ludwig Lecture: pathophysiology of the human sympathetic nervous system in cardiovascular diseases: the transition from mechanisms to medical management. J Appl Physiol. 2010;108(2):227-237.

Dibona GF, Esler MD. Translational Medicine: the antihypertensive effect of renal denervation. Am J Physiol Regul Integr Comp Physiol. 2010;298(2):R245-253.

Katholi RE, Rocha-Singh KJ. The role of renal sympathetic nerves in hypertension: has percutaneous renal denervation refocused attention on their clinical significance? Prog Cardiovasc Dis. 2009;52(3):243-248.

Doumas M, Faselis C, Papademetriou V. Renal Sympathetic Denervation and Systemic Hypertension. Am J Cardiol. 2010;105(4):570-576.

Schlaich MP, Krum H, Sobotka PA. Renal sympathetic nerve ablation: the new frontier in the treatment of hypertension. Curr Hypertens Rep. 2010;12(1):39-46.

Katholi RE, Rocha-Singh KJ, Goswami NJ, Sobotka PA. Renal nerves in the maintenance of hypertension: A potential therapeutic target. Curr Hypertens Rep. 2010;12:196-204.

Esler MD, Lambert EA, Schlaich M, Navar LG. The Dominant Contributor to Systemic Hypertension: Chronic Activation of the Sympathetic Nervous System vs Activation of the Intrarenal Renin-Angiotensin System. J Appl Physiol. 2010.

Fisher JP, Fadel PJ. Therapeutic strategies for targeting excessive central sympathetic activation in human hypertension. Exp Physiol. 2010;95(5):572-580.

Malpas SC. Sympathetic nervous system overactivity and its role in the development of cardiovascular disease. Physiol Rev. 2010;90:513-557.

Lambert GW, Straznicky NE, Lambert EA, Dixon JB, Schlaich MP. Sympathetic nervous activation in obesity and the metabolic syndrome–causes, consequences and therapeutic implications. Pharmacol Ther. 2010;126:159-172.

Masuo K, Lambert GW, Esler MD, Rakugi H, Ogihara T, Schlaich MP. The role of sympathetic nervous activity in renal injury and end-stage renal disease. Hypertens Res. 2010;33:521-528.

Schlaich MP, Socratous F, Hennebry S, Eikelis N, Lambert EA, Straznicky N, Esler MD, Lambert GW. Sympathetic activation in chronic renal failure. J Am Soc Nephrol. 2009;20(5):933-939.

Bock JS, Gottlieb SS. Cardiorenal syndrome: New perspectives. Circulation. 2010;121:2592-2600.

Goldsmith SR, Sobotka PA, Bart BA. The sympathorenal axis in hypertension and heart failure. Journal of Cardiac Failure. 2010;16(5):369-373.

Grassi G. Assessment of sympathetic cardiovascular drive in human hypertension: achievements and perspectives. Hypertension. 2009;54(4):690-697.

Ritz E. New approaches to pathogenesis and management of hypertension. Clin J Am Soc Nephrol. 2009;4(12):1886-1891.

Ritz E, Rump LC. Control of sympathetic activity–new insights; new therapeutic targets? Nephrol Dial Transplant. 2010;25(4):1048-1050.

Joyner MJ, Charkoudian N, Wallin BG. Sympathetic nervous system and blood pressure in humans: Individualized patterns of regulation and their implications. Hypertension. 2010;56:10-16.

Mann JF. Whats new in hypertension 2009? Nephrol Dial Transplant. 2010;25(1):37-41.

Bravo EL, Rafey MA, Nally JV, Jr. Renal denervation for resistant hypertension. Am J Kidney Dis. 2009;54(5):795-797.

King A. Hypertension: RF ablation of renal nerves. Nature Reviews Nephrology. 2009;5:364.

Doumas M, Douma S. Interventional management of resistant hypertension. Lancet. 2009;373(9671):1228-1230.

Paulis L. Novel therapeutic targets for hypertension. Nat Rev Cardiol. 2010.

OBrien E. Renal sympathetic denervation for resistant hypertension. Lancet. 2009;373(9681):2109; author reply 2109-2110.

Titze S, Uder M, Schmieder R. Renal nerve ablation: innovative therapy for treatment of resistant hypertension. MMW Fortschr Med. 2009;151(42):52-53.

Katona PG. Biomedical engineering in heart-brain medicine: A review. Cleve Clin J Med. 2010;77 Suppl 3:S46-50.

Abstracts about Renal Denervation Treatment

Schlaich M, Krum H, Walton T, Whitbourn R, Sobotka P, Esler M. Two-year durability of blood pressure reduction with catheter-based renal sympathetic denervation. Journal of Hypertension. 2010;28:e446.

Esler M, Schlaich M, Sobotka P, Whitbourn R, Sadowski J, Bartus K, et al. Catheter-Based Renal Denervation Reduces Total Body and Renal Noradrenaline Spillover and Blood Pressure in Resistant Hypertension. Journal of Hypertension. 2009;27(suppl 4):s167.

Schlaich MP, Krum H, Whitbourn R, Walton T, Lambert GW, Sobotka PA, et al. Effects of Renal Sympathetic Denervation on Noradrenaline Spillover and Systemic Blood Pressure in Patients with Resistant Hypertension. Journal of Hypertension. 2009;27(suppl 4):s154.

Schlaich M, Krum H, Walton T, Lambert E, Lambert G, Sobotka P, et al. A Novel Catheter Based Approach to Denervate the Human Kidney Reduces Blood Pressure and Muscle Sympathetic Nerve Activity in a Patient with End Stage Renal Disease and Hypertension. Journal of Hypertension. 2009;27(suppl 4):s437.

 

Read Full Post »

« Newer Posts