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Archive for the ‘Frontiers in Cardiology and Cardiovascular Disorders’ Category


Targeting Atherosclerotic Plaques with Stents made of Drug-eluting Biomaterials

Reporter: Daniel Menzin, BSc BioMedical Engineering, expected, May 2021, Research Assistant 4, Core Applications Developer and Acting CTO 

 

Atherosclerosis is a chronic cardiovascular disease with a multitude of different implications. A coronary artery plaque may lead to congestive heart failure while an aortic plaque may cause angina. Both can quite possibly lead to a heart attack unless properly managed. One way to manage this condition is through the use of stents made of a mesh that is expanded following placement into the diseased vessel.

Unfortunately, stents are oftentimes initially effective but eventually restenosis occurs. Restenosis is a condition in which the affected vessel becomes blocked again. Cholesterol-rich blood vessel environments oftentimes lead to an irritation that results in white blood cells aggregating in the area and releasing proinflammatory chemokines and cytokines, which cause fibrosis. To make matters worse, the cholesterol plaques undergo compression against the vessel wall which causes vessel injury and further inflammation. This leads to thrombus formation and may potentiate neointimal hyperplasia, an abnormal proliferation and migration of smooth muscle cells in the tunica intima. Neointimal hyperplasia plays a major role in restenosis.

Recent research has found that interfacing drug eluting biomaterials with stents may help prevent restenosis. One study showed that rapamycin delivered with acid labile and ROS-sensitive forms of Beta-cyclodextrin produced promising results when treating atherosclerosis in rat models (Dou, et al). In this promising new paradigm of treatment, non-proinflammatory biomaterials are interfaced with stents. Once inflammation appears the biomaterial will begin to degrade, slowly releasing the drug which suppresses the underlying immune reaction and the resulting inflammation.

 

SOURCE

Dou Y;Chen Y;Zhang X;Xu X;Chen Y;Guo J;Zhang D;Wang R;Li X;Zhang J; “Non-Proinflammatory and Responsive Nanoplatforms for Targeted Treatment of Atherosclerosis.” Biomaterials, U.S. National Library of Medicine, 29 July 2017, pubmed.ncbi.nlm.nih.gov/28778000/.

 

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

75 articles found in the search 

https://pharmaceuticalintelligence.com/?s=drug+eluting+stents

 

Among them:

Stent Design and Thrombosis:  Bifurcation Intervention, Drug Eluting Stents (DES) and Biodegrable Stents

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/06/stent-design-and-thrombosis-bifurcation-intervention-drug-eluting-stents-des-and-biodegrable-stents/

 

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

Author: Larry H Bernstein, MD, FACP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/04/25/contributions-to-vascular-biology/

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via Dr. Giordano Featured in Forbes Article on COVID-19 Antibody Tests in Italy and USA

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Clinical Trial for the Use of Nitric Oxide to Treat Severe COVID-19 Infection

Reporter and Curator: Aviva Lev-Ari, PhD, RN

 

UPDATED 5/26/2020

2009 Dec 5;395(1):1-9.

doi: 10.1016/j.virol.2009.09.007. Epub 2009 Oct 1.

Dual Effect of Nitric Oxide on SARS-CoV Replication: Viral RNA Production and Palmitoylation of the S Protein Are Affected

Affiliations expand

Free PMC article

Abstract

Nitric oxide is an important molecule playing a key role in a broad range of biological process such as neurotransmission, vasodilatation and immune responses. While the anti-microbiological properties of nitric oxide-derived reactive nitrogen intermediates (RNI) such as peroxynitrite, are known, the mechanism of these effects are as yet poorly studied. Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) belongs to the family Coronaviridae, was first identified during 2002-2003. Mortality in SARS patients ranges from between 6 to 55%. We have previously shown that nitric oxide inhibits the replication cycle of SARS-CoV in vitro by an unknown mechanism. In this study, we have further investigated the mechanism of the inhibition process of nitric oxide against SARS-CoV. We found that peroxynitrite, an intermediate product of nitric oxide in solution formed by the reaction of NO with superoxide, has no effect on the replication cycle of SARS-CoV, suggesting that the inhibition is either directly effected by NO or a derivative other than peroxynitrite. Most interestingly, we found that NO inhibits the replication of SARS-CoV by two distinct mechanisms.

  • Firstly, NO or its derivatives cause a reduction in the palmitoylation of nascently expressed spike (S) protein which affects the fusion between the S protein and its cognate receptor, angiotensin converting enzyme 2.
  • Secondly, NO or its derivatives cause a reduction in viral RNA production in the early steps of viral replication, and this could possibly be due to an effect on one or both of the cysteine proteases encoded in Orf1a of SARS-CoV.

 

UPDATED ON 4/21/2020

A Possible Explanation for the COVID-19 Racial Disparity

— And a possible solution

While the pathophysiology of hypertension is complex and multifaceted, there are notable racial differences. In the context of COVID-19, the most suspicious difference is a comparative deficiency of L-arginine and subsequently nitric oxide (NO). In this lies a potential explanation for the COVID-19 race disparity

NO is a gas synthesized by our cells and has multiple roles, but perhaps is best known for vascular dilation. In short, NO facilitates relaxation of vascular smooth muscle allowing vessel dilation and increased blood flow.

This on its own has potential implications in acute respiratory distress syndrome (ARDS), a condition that results from severe COVID-19 infection. By improving blood flow across the entire lung, this theoretically results in improved gas exchange and oxygenation of the blood. In fact, there is research that inhaled NO improved oxygenation and other clinical outcomes in SARS-1 patients, and current research in COVID-19 coronavirus (SARS-CoV-2) supports this previously demonstrated efficacy.

Additionally, abnormal blood clotting is an increasingly recognized complication of this disease, both systemically and within the pulmonary circulation. In fact, one of the greatest predictors of death is a serum blood test that indicates elevated clotting activity. Most recently, some physicians have suggested that small clots within the lungs are central to pathogenesis and have administered clot busting drugs known as thrombolytics which abruptly improve oxygenation, albeit transiently, as the medication effect weans and the predisposition to clot formation persists. NO inhibits clot formation, and deficiency may contribute to a prothrombotic state. In fact, it has been shown that inhaled NO decreases the propensity of clotting in ARDS.

However, perhaps the most convincing role of nitric oxide in this disease is its antiviral properties. SARS-CoV-2 infects cells by attaching to a receptor on the lining of the airways called angiotensin-converting enzyme 2 (ACE2). This is the same mechanism by which SAR-1 infects cells. NO specifically alters a surface protein on SARS-1, known as the spike protein, such that it cannot attach to the ACE2 receptor. This results in blocking viral entry into the cell as well as the subsequent replication of the virus. Since SARS-CoV-2 shares the same mechanism of cell entry, we can relatively confidently assume that NO would have a similar effect regarding this novel virus.

Knowing that NO deficiency is common in African Americans and that this population is disproportionately dying from an infection that can be blocked by this gas, augmenting NO seems like a reasonable therapeutic target. While NO is being used as an inhaled gas via mechanical ventilation, this is only suitable for someone ill enough to require mechanical ventilation.

A better way to increase nitric oxide in the minimally ill or even uninfected is to augment the body’s ability to create it. There are many pharmacologic ways to do this; however, potentially the most effective, cheapest, and lowest risk is to supplement with the precursor amino-acids L-arginine and L-citrulline. We already know these nutritional supplements result in this very effect and that there seems to be a more potent effect of supplementation on NO production in L-arginine-deficient African Americans.

Therefore, a reasonable action is to expedite clinical trials to further investigate this theory. At a minimum, we need to start a conversation to improve our understanding of the role of nitric oxide deficiency as a risk factor for disease severity. It is my strong belief that augmenting NO via L-arginine and L-citrulline not only has potential for treatment and reducing progression to severe illness, but given the safety profile, it may be most valuable as a preventative measure.

It could save many lives at a minimal cost.

Jason Kidde, MS, MPAS, is a physician assistant at University of Utah Health in Salt Lake City.

Last Updated April 21, 2020
SOURCE

 

Previous research found nitric oxide has antiviral properties against coronaviruses.

ummary: A new clinical trial is enrolling patients with severe COVID-19 symptoms to assess the effect of nitric oxide in treating the virus. Previous research found nitric oxide has antiviral properties against coronaviruses. The effect was tested and demonstrated during the SARS outbreak in the early 2000s.

Source: University of Alabama at Birmingham

The University of Alabama at Birmingham has been selected to begin enrolling patients in an international study assessing the use of inhaled nitric oxide (iNO) to improve outcomes for COVID-19 patients with severely damaged lungs.

iNO has been used for the treatment of failing lungs, but it was also found to have antiviral properties against coronaviruses

“In humans, nitric oxide is generated within the blood vessels and regulates blood pressure, and prevents formation of clots and also destroys potential toxins,” Arora said.

The UAB team says this pandemic has led to an extraordinary unifying response by the medical community, including ICU physicians, nurses, respiratory therapists, clinical trial specialists, reviewers and medical administrators, allowing for faster than normal approvals for potentially lifesaving research studies.

“The fact that we are able to get this trial started quickly was due to collaborations across specialties and fields of expertise at UAB with the common goal of providing the highest quality of scientifically proven care for our COVID-19 patients,” Arora said. “We are all trying to fight this together, and I hope, with our resilience, we shall overcome these difficult times.”

SOURCE
Source:
University of Alabama at Birmingham
Media Contacts:
Adam Pope – University of Alabama at Birmingham
Image Source:
The image is credited to University of Alabama at Birmingham.

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

  • Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market: Clinical Outcomes after Use of iNO in the Institutional Market, Therapy Demand and Cost of Care vs. Existing Supply Solutions

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/03/clinical-indications-for-use-of-inhaled-nitric-oxide-ino-in-the-adult-patient-market-clinical-outcomes-after-use-therapy-demand-and-cost-of-care/

 

Series A: e-Books on Cardiovascular Diseases

 

BUNDLED BY AMAZON.COM INTO A SIX-VOLUME SERIES FOR $515

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Six Volumes

  1. Cardiovascular Diseases, Volume One: Perspectives on Nitric Oxide in Disease Mechanisms. On com since 6/21/2013 https://lnkd.in/8DANfq
  2. Cardiovascular Diseases, Volume Two: Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation. On com since 11/30/2015 https://lnkd.in/ekbuNZ3
  3. Cardiovascular Diseases, Volume Three: Etiologies of Cardiovascular Diseases: Epigenetics, Genetics and Genomics. On com since 11/29/2015 https://lnkd.in/ecp5mrA
  4. Cardiovascular Diseases, Volume Four: Regenerative and Translational Medicine: The Therapeutics Promise for Cardiovascular Diseases. On com since 12/26/2015 https://lnkd.in/dwqM3K3
  5. Cardiovascular Diseases, Volume Five: Pharmacological Agents in Treatment of Cardiovascular Diseases. On com since 12/23/2018 https://lnkd.in/e3r87cQ
  6. Cardiovascular Diseases, Volume Six: Interventional Cardiology for Disease Diagnosis and Cardiac Surgery for Condition Treatment. On com since 12/24/2018 https://lnkd.in/e_CTb4R

  • Cardiovascular Diseases, Volume One: Perspectives on Nitric Oxide in Disease Mechanisms. On Amazon.com since 6/21/2013

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

Perspectives on Nitric Oxide in Disease Mechanisms (Biomed e-Books Book 1) by [Margaret Baker PhD, Tilda Barliya PhD, Anamika Sarkar PhD, Ritu Saxena PhD, Stephen J. Williams PhD, Larry Bernstein MD FCAP, Aviva Lev-Ari PhD RN, Aviral Vatsa PhD]

Perspectives on Nitric Oxide in Disease Mechanisms (Biomed e-Books Book 1) Kindle Edition

Table of Contents

Chapter 1:

Nitric Oxide Basic Research

1.1 Discovery of Nitric Oxide

1.1.1 Discovery of Nitric Oxide and its Role in Vascular Biology

Aviral Vatsa, PhD, MBBS

1.1.2 Nitric Oxide: The Nobel Prize in Physiology or Medicine

Aviva Lev-Ari, PhD, RN

1.2 Nitric Oxide Synthase(s)

1.2.1 Nitric Oxide: A Short Historic Perspective

Aviral Vatsa, PhD, MBBS

1.2.2 Nitric Oxide: Role in Cardiovascular Health and Disease

Aviral Vatsa, PhD, MBBS

1.3 Endothelial Blood Cell Interactions: Platelet, Leukocyte and Monocyte

1.3.1 Nitric Oxide: Chemistry and Function

Aviral Vatsa, PhD, MBBS

1.4 Signaling Pathways

1.4.1 Nitric Oxide Signaling Pathways

Aviral Vatsa, PhD, MBBS

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

Larry H. Bernstein, MD, FCAP

1.5 Oxidative Stress

1.5.1 Mitochondrial Damage and Repair under Oxidative Stress

Larry H. Bernstein, MD, FCAP

1.6 Oxygen and Nitrogen Reactive Species

1.6.1 Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium

Larry H Bernstein, MD, FCAP

1.6.2 Prostacyclin and Nitric Oxide: Adventures in vascular biology –  a tale of two mediators

Aviva Lev-Ari, PhD, RN

 

Chapter 2:

Nitric Oxide and Circulatory Diseases

2.1 Endothelial Dysruption and Denudation

2.1.1 Blood-vessels-generating Stem Cells Discovered

Ritu Saxena, PhD

2.1.2 Differential Distribution of Nitric Oxide – A 3-D Mathematical Model

Anamika Sarkar, PhD

2.1.3 Nitric Oxide Nutritional Remedies for Hypertension and Atherosclerosis. It’s 12AM: Do you know where your electrons are?

Meg Baker, PhD

2.2 Endothelin and ET Receptors

2.2.1 Statins’ Nonlipid Effects on Vascular Endothelium through eNOS Activation

Larry H Bernstein, MD, FCAP

2.2.2 Endothelial Function and Cardiovascular Disease

Larry H Bernstein, MD, FCAP

2.2.3 Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation: Observations on Intellectual Property Development for an Unrecognized Future Fast Acting Therapy for Patients at High Risk for Macrovascular Events

Aviva Lev-Ari, PhD, RN

Chapter 3:

Therapeutic Cardiovascular Targets

3.1 Nitric oxide and therapeutic Targets

3.1.1 Cardiovascular Disease (CVD) and the Role of Agent Alternatives in Endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production

Aviva Lev-Ari, PhD, RN

3.1.2 Telling NO to Cardiac Risk

Stephen W Williams, PhD

3.1.3 Nitric Oxide and its Impact on Cardiothoracic Surgery

Tilda Barliya PhD

3.2 Therapeutic opportunities for Endothelial Progenitor Cells

3.2.1 Inhibition of ET-1, ETA and ETA-ETB, Induction of Nitric Oxide production, stimulation of eNOS and Treatment Regime with PPAR-gamma agonists (TZD): eEPCs Endogenous Augmentation for Cardiovascular Risk Reduction – A Bibliography

Aviva Lev-Ari, PhD, RN

3.2.2 Bystolic’s generic Nebivolol – Positive Effect on circulating Endothelial Progenitor Cells Endogenous Augmentation

Aviva Lev-Ari, PhD, RN

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

Aviva Lev-Ari, PhD, RN

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

Aviva Lev-Ari, PhD, RN

3.3 Hypertension, Congestive Heart Failure and Endothelin Biomarker

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

Aviva Lev-Ari, PhD, RN

3.4 Hypotension and Shock: Cardiovascular Collapse

3.4.1 Nitric Oxide and Sepsis, Hemodynamic Collapse and the Search for Therapeutic Options

Larry H Bernstein, MD, FCAP

3.4.2 Sepsis, Multi-organ Dysfunction Syndrome, and Septic Shock: A Conundrum of Signaling Pathways Cascading Out of Control

Larry H Bernstein, MD, FCAP

3.5 Hemorrhagic and Thrombo-embolic Events

3.5.1 Nitric Oxide Function in Coagulation

Larry H Bernstein, MD, FCAP

Chapter 4:

Nitric Oxide and Neurodegenerative Diseases

4.1 Nitric Oxide Covalent Modifications: A Putative Therapeutic Target?

Stephen J. Williams, PhD

Chapter 5:

Bone Metabolism

5.1 Nitric Oxide in Bone Metabolism

Aviral Vatsa, PhD, MBBS

Chapter 6:

Nitric Oxide and Systemic Inflammatory Disease

6.1 Nitric Oxide and Immune Responses: Part 1

Aviral Vatsa, PhD, MBBS

6.2 Nitric Oxide and Immune Responses: Part 2

Aviral Vatsa, PhD, MBBS

6.3 Nitric Oxide Production in Systemic Sclerosis

Aviral Vatsa, PhD. MBBS

Chapter 7:

Nitric Oxide: Lung and Alveolar Gas Exchange

7.1 ’Lung on a Chip’

Ritu Saxena, Ph.D.

7.2 Low Bioavailability of Nitric Oxide due to Misbalance in Cell Free Hemoglobin in Sickle Cell Disease – A Computational Model

Anamika Sarkar, Ph.D.

7.3 The Rationale and Use of Inhaled Nitric Oxide in Pulmonary Artery Hypertension and Right Sided Heart Failure

Larry H Bernstein, MD, FCAP

7.4 Transposon-mediated Gene Therapy improves Pulmonary Hemodynamics and attenuates Right Ventricular Hypertrophy: eNOS gene therapy reduces Pulmonary vascular remodeling and Arterial wall hyperplasia

Aviva Lev-Ari, PhD, RN

Chapter 8:

Nitric Oxide and Kidney Dysfunction

8.1 Part I: The Amazing Structure and Adaptive Functioning of the Kidneys: Nitric Oxide

Larry H. Bernstein, MD, FCAP

8.2 Part II: Nitric Oxide and iNOS have Key Roles in Kidney Diseases

Larry H. Bernstein, MD, FCAP

8.3 Part III: The Molecular Biology of Renal Disorders: Nitric Oxide

Larry H. Bernstein, MD, FCAP

8.4 Part IV: New Insights on Nitric Oxide Donors

Larry H. Bernstein, MD, FCAP

8.5 The Essential Role of Nitric Oxide and Therapeutic Nitric Oxide Donor Targets in Renal Pharmacotherapy

Larry H. Bernstein, MD, FCAP

Chapter 9:

Nitric Oxide and Cancer

9.1 Crucial role of Nitric Oxide in Cancer

Ritu Saxena, Ph.D.

Summary

Nitric oxide and its role in vascular biology

 

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Imaging (ECHO) marker that would identify early cardiotoxic effects: The impact of high-dose immunosuppression for ICI myocarditis Cardiac Echo Tracks Checkpoint Inhibitor Damage – Predicting cardiac injury before EF falls

Reporter: Aviva Lev-Ari, PhD, RN

The present study is the first to use Global longitudinal strain (GLS) specifically to identify immune checkpoint inhibitors (ICI) myocarditis, Abraham and Aras noted.

The study compared 101 ICI myocarditis cases from a multicenter international registry (30 with serial GLS) against a random sample of 92 ICI users at Neilan’s institution who did not present with myocarditis (14 with serial GLS) during a study period from 2013 through 2019.

Despite not propensity-matching these patients, the investigators ended up with two groups with similar age (around 65), sex (>60% men), and cancer type (most commonly melanoma and lung cancer).

Before ICI therapy, GLS was similar between groups (20.3% among cases and 20.6% among controls, P=0.60).

Patients who had myocarditis still had a normal ejection fraction in 60% of cases.

One major limitation of the study was that serial echocardiograms had not been routinely performed on people with myocarditis. “[T]hus, it was not possible to determine if the GLS decrease occurred prior to the development of myocarditis,” Neilan and colleagues acknowledged.

Furthermore, 97% of ICI myocarditis cases presented with elevated troponin levels, so it’s “unclear if GLS assessment has incremental value to such readily available biomarkers,” the editorialists pointed out.

“Additional work is needed to test if the GLS decrease occurs prior to the development of clinical myocarditis, can provide an early method of detection, and whether tailoring immunosuppressive therapy based on the measurement of GLS at presentation with myocarditis may be of value,” the authors said.

 

SOURCES

 

  • Cardiac Echo Tracks Checkpoint Inhibitor Damage

https://www.medpagetoday.com/cardiology/chf/84682?xid=nl_mpt_DHE_2020-02-04&eun=g99985d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=Daily%20Headlines%20Top%20Cat%20HeC%20%202020-02-04&utm_term=NL_Daily_DHE_dual-gmail-definition

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Reporter: Gail S. Thornton, M.A.

Studies have shown that regular physical activity can contribute to longer life and less risk for serious health problems, such as heart disease, type 2 diabetes, obesity and some cancers.  The Centers for Disease Control (CDC) continues to partner with national groups, states and communities to provide quality education around the physical activity.

An analysis, Adult Physical Inactivity Prevalence Maps by Race/Ethnicity, published on the CDC web site in January 2020 demonstrated that “all states and territories had more than 15 percent of adults who were physically inactive.” The analysis included state maps that used combined data from 2015 through 2018 with “noticeable differences in the prevalence of physical inactivity by race/ethnicity.” Physical inactivity is reported as “no leisure-time physical activity.”

Here are findings from their analysis:

  • The South (28.0%) had the highest prevalence of physical inactivity, followed by the Northeast (25.6%), Midwest (25.0%), and the West (20.5%).
  • In 7 states (Tennessee, Oklahoma, Louisiana, Alabama, Kentucky, Arkansas, and Mississippi), and 2 US territories (Puerto Rico, and Guam), 30% or more of adults were physically inactive.
  • In 4 states (Colorado, Washington, Utah, and Oregon) and the District of Columbia, 15% to less than 20% of adults were physically inactive.
  • In 24 states, 20% to less than 25% of adults were physically inactive.
  • In 15 states, 25% to less than 30% of adults were physically inactive.

More analysis showed:

  • Hispanics (31.7%) had the highest prevalence of physical inactivity, followed by non-Hispanic blacks (30.3%) and non-Hispanic whites (23.4%).
  • In the majority of states, non-Hispanic blacks and Hispanics had a significantly higher prevalence of inactivity than non-Hispanic whites.
  • 5 states and Puerto Rico had a physical inactivity prevalence of 30% or higher among non-Hispanic white adults.

###

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Genetic Testing in CVD and Precision Medicine

Reporter: Aviva Lev-Ari, PhD, RN

 

See


Series A: e-Books on Cardiovascular Diseases
 

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

VOLUME THREE

Etiologies of Cardiovascular Diseases:

Epigenetics, Genetics and Genomics

http://www.amazon.com/dp/B018PNHJ84

by  

Larry H Bernstein, MD, FCAP, Senior Editor, Author and Curator

and

Aviva Lev-Ari, PhD, RN, Editor and Curator

Genetic Testing in CVD and Precision Medicine

Based on

. 2018 Apr; 3(2): 313–326.
Published online 2018 May 30. doi: 10.1016/j.jacbts.2018.01.003
PMCID: PMC6059349
PMID: 30062216

Cardiovascular Precision Medicine in the Genomics Era

Alexandra M. Dainis, BSa and Euan A. Ashley, BSc, MB ChB, DPhila,b,c,

 

In 2010, we introduced an approach to the evaluation of a personal genome in a clinical context . A patient with a family history of coronary artery disease (CAD) and sudden death was evaluated by a cardiac clinical team in conjunction with whole genome sequencing and interpretation. The genomic analysis revealed an increased genetic risk for myocardial infarction and type 2 diabetes. In addition, a pharmacogenomics analysis was performed to assess how the genetics of the patient might influence response to certain drugs, including lipid-lowering therapies and warfarin . This clinical assessment, which focused heavily on cardiovascular risk, suggested that whole genome sequencing might provide clinically relevant information for patients.

A 2011 joint statement from the Heart Rhythm Society and the European Heart Rhythm association recommended genetic testing as a class I indication for patients with a number of channelopathies and cardiomyopathies, including long QT syndrome (LQTS), arrhythmogenic right ventricular cardiomyopathy, familial dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy (HCM) . Similarly, a statement from the American Heart Association and the American College of Cardiology recommended genetic testing for HCM, DCM, and thoracic aortic aneurysms to facilitate familial cascade screening and deduce causative mutations .

The diagnostic power of genetic testing is significant across the spectrum of CVDs, ranging from cardiomyopathies to life-threatening arrhythmias . In the clinic, genetic testing can:

  • 1.

    clarify disease diagnoses: genetic testing can help to clarify the diagnosis of diseases that cause similar clinical presentation (e.g., cardiac hypertrophy could be TTR amyloidosis, Fabry disease, or sarcomeric HCM);

  • 2.

    facilitate cascade screening: genetic testing can help to identify relatives at risk for CVD before disease symptoms manifest if a disease-associated variant is found in a proband and then screened for in relatives;

  • 3.

    direct more precise therapy: genetic testing can help physicians choose appropriate treatments and plan appropriate timing of those treatments. For example, inherited connective tissue disease due to variants in ACTA2MYH11, or TGFBR2 might prompt consideration of surgical intervention at a smaller aortic aneurysm diameter ; and

  • 4.

    identify patients for targeted therapies: targeted medical therapies, including antibody-based therapeutics, gene editing, and silencing technologies, are available or under development for several genetic diseases, including LQTS, Duchenne muscular dystrophy (DMD), TTR cardiac amyloidosis , and Fabry disease .

REFERENCES

7. Ashley E.A., Butte A.J., Wheeler M.T. Clinical assessment incorporating a personal genome. Lancet. 2010;375:1525–1535. [PMC free article] [PubMed[]
8. Ackerman M.J., Priori S.G., Willems S. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA) Europace. 2011;13:1077–1109. [PubMed[]
9. Gersh B.J., Maron B.J., Bonow R.O. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011;58:2703–2738. [PubMed[]
10. Harper A.R., Parikh V.N., Goldfeder R.L., Caleshu C., Ashley E.A. Delivering clinical grade sequencing and genetic test interpretation for cardiovascular medicine. Circ Cardiovasc Genet. 2017;10(2) [PubMed[]
11. Walsh R., Thomson K.L., Ware J.S. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017;19:192–203. [PMC free article] [PubMed[]
12. Sturm A.C., Hershberger R.E. Genetic testing in cardiovascular medicine: current landscape and future horizons. Curr Opin Cardiol. 2013;28:317–325. [PubMed[]
13. Caleshu C., Ashley E. Genetic testing for cardiovascular conditions predisposing to sudden death. In: Wilson M.G., Drezner J., editors. IOC Manual of Sports Cardiology. Wiley & Sons, Ltd; Hoboken, NJ: 2016. pp. 175–186. []
14. Benson M.D., Dasgupta N.R., Rissing S.M., Smith J., Feigenbaum H. Safety and efficacy of a TTR specific antisense oligonucleotide in patients with transthyretin amyloid cardiomyopathy. Amyloid. 2017;24:217–223. [PubMed[]
15. Parikh V.N., Ashley E.A. Next-generation sequencing in cardiovascular disease: present clinical applications and the horizon of precision medicine. Circulation. 2017;135:406–409. [PMC free article] [PubMed[]

SOURCE

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059349/

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Risks from Dual Antiplatelet Therapy (DAPT) may be reduced by Genotyping Guidance of Cardiac Patients

Reporter: Aviva Lev-Ari, PhD, RN

 

Genotyping Cardiac Patients May Reduce Risks From DAPT

-STEMI patient study reaches noninferiority mark for adverse cardiac events

In the investigational arm, all 1,242 patients were tested for CYP2C19 loss-of-function alleles *2 or *3. Carriers received ticagrelor or prasugrel, while noncarriers received clopidogrel, considered to be less powerful.

No genetic testing was performed in the standard treatment arm (n=1,246), in which patients largely went on to receive ticagrelor or prasugrel. Nearly all patients in both cohorts received dual antiplatelet therapy (DAPT) with aspirin.

Following primary PCI, patients went on to the P2Y12 inhibitor for at least 12 months, with drug adherence similar between the genotype-guided (84.5%) and standard groups (82.0%).

For patients with CYP2C19 loss-of-function alleles in the genotype-guided arm, 38% received ticagrelor and 1% received prasugrel. The remaining 61% of patients — the noncarriers — received clopidogrel. In the control arm, 91% were treated with ticagrelor, 2% with prasugrel, and 7% with clopidogrel, according to local protocol.

Ten Berg said that prasugrel is not typically used in the Netherlands, where eight of the centers in the trial were located, but that this might change given that the drug lowered rates of ischemic events versus ticagrelor in the head-to-head ISAR REACT 5 trial, which was also presented at ESC.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco

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Injectable inclisiran (siRNA) as 3rd anti-PCSK9 behind mAbs Repatha and Praluent

 

Reporter: Aviva Lev-Ari, PhD, RN

Next stop, filing for approval. The Medicines Company has said it plans to submit inclisiran for FDA review by the end of 2019 and EMA review in the first quarter of 2020. If the drug’s approved it’ll be the third anti-PCSK9 behind mAbs Repatha and Praluent, and could try to compete on price to gain market share.

The company’s been very careful not to disclose its pricing plans for inclisiran, said ORION-10 principal investigator Dr. Scott Wright, professor and cardiologist at the Mayo Clinic. But, Wright said, The Medicines Co. and other companies he advises on clinical trial design “have learned the lesson from the sponsors of the monoclonal antibodies [against PCSK9], they’re not going to come in and price a drug that’s out of proportion to what the market will bear.” 

Because the anti-PCSK9 mAbs were initially priced beyond what patients and insurers were willing to pay, “now most of the physicians that I meet have a resistance to using them just because they’re fearful about the pre-approval process” with insurers, said Wright. “They’re much easier to get approved and paid for today than they’ve ever been, but that message is not out in the medical community yet.”

SOURCE

From: “STAT: AHA in 30 Seconds” <newsletter@statnews.com>

Reply-To: “STAT: AHA in 30 Seconds” <newsletter@statnews.com>

Date: Monday, November 18, 2019 at 2:59 PM

To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

Subject: Interim look at Amarin data, an inclisiran update, & Philly’s giant heart

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Transthyretin amyloid cardiomyopathy (ATTR-CM): U.S. FDA APPROVES VYNDAQEL® AND VYNDAMAX™ for this Rare and Fatal Disease

 

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 11/22/2019

Trialists Attack $225K Heart Drug Price Tag

Cardiologists who helped run the pivotal study of Pfizer’s heart drug tafamidis (Vyndaqel/Vyndamax) are criticizing the drug’s $225,000 annual price tag, Bloomberg reports.

Mathew Maurer, MD, of Columbia University, and three other doctors involved in the trial started speaking out after seeing patients’ financial struggles after the drug’s market launch earlier this year.

For example: John Rufenacht, a 73-year-old interior designer in Kansas City, Missouri, has Medicare but his out-of-pocket cost was $6,000 for a 90-day supply of the drug, which treats cardiac transthyretin amyloidosis. Rufenacht doesn’t qualify for Pfizer’s patient assistance programs, most of which direct patients to charities to help them pay.

Maurer aired his complaints in front of colleagues at the Heart Failure Society of America meeting in September, and at the American Heart Association meeting earlier this week, where he and colleagues reported a cost-effectiveness study on the drug, showing it’s only cost-effective with a more than 90% price reduction — a cost of $16,563 a year.

Pfizer says its price is appropriate, given the small number of patients in the U.S. with the condition who will receive it — some 100,000 to 150,000, the company estimates. But Maurer and critics say that’s likely an underestimate. Diagnosis requires an invasive heart biopsy; there was little incentive to do that when no approved treatment was available.

The company promised to cut the price if more patients start taking the drug.

SOURCE

https://www.medpagetoday.com/publichealthpolicy/ethics/83459?xid=nl_badpractice_2019-11-22&eun=g99985d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=BadPractice_112219&utm_term=NL_Gen_Int_Bad_Practice%20-%20Active

 

Click here to learn more about Pfizer’s Rare Disease portfolio and how we empower patients, engage communities in our clinical development programs, and support programs that heighten disease awareness.

 

U.S. FDA APPROVES VYNDAQEL® AND VYNDAMAX™ FOR USE IN PATIENTS WITH TRANSTHYRETIN AMYLOID CARDIOMYOPATHY, A RARE AND FATAL DISEASE

— First and only medicines approved for patients with either wild-type or hereditary transthyretin amyloid cardiomyopathy —

Monday, May 6, 2019 – 6:45am
EDT

NEW YORK–(BUSINESS WIRE)–Pfizer Inc. (NYSE:PFE) announced today that the U.S. Food and Drug Administration (FDA) has approved both VYNDAQEL® (tafamidis meglumine) and VYNDAMAX (tafamidis) for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization. VYNDAQEL and VYNDAMAX are two oral formulations of the first-in-class transthyretin stabilizer tafamidis, and the first and only medicines approved by the FDA to treat ATTR-CM.

Transthyretin amyloid cardiomyopathy is a rare, life-threatening disease characterized by the buildup of abnormal deposits of misfolded protein called amyloid in the heart and is defined by restrictive cardiomyopathy and progressive heart failure. Previously, there were no medicines approved to treat ATTR-CM; the only available options included symptom management, and, in rare cases, heart (or heart and liver) transplant. It is estimated that the prevalence of ATTR-CM is approximately 100,000 people in the U.S. and only one to two percent of those patients are diagnosed today.

“The approvals of VYNDAQEL and VYNDAMAX are a testament to the significant research and development investment in our innovative cardiovascular outcomes trial, ATTR-ACT. We are proud to bring these medicines to ATTR-CM patients who are in dire need of treatment,” said Brenda Cooperstone, MD, Senior Vice President and Chief Development Officer, Rare Disease, Pfizer Global Product Development. “VYNDAQEL and VYNDAMAX reduce cardiovascular mortality and the frequency of cardiovascular-related hospital stays in patients with wild-type or hereditary forms of this rare disease, giving them a chance for more time with their loved ones.”

“Pfizer’s purpose is to deliver breakthrough medicines that change patients’ lives. The approvals of VYNDAQEL and VYNDAMAX deliver on this promise for patients with ATTR-CM,” said Paul Levesque, Global President, Rare Disease. “This milestone is a gamechanger for patients, who until today had no approved medicines for this rare, debilitating and fatal disease. We will continue to focus efforts on working with the physician community to increase awareness and ultimately detection and diagnosis of this disease.”

The recommended dosage is either VYNDAQEL 80 mg orally once-daily, taken as four 20 mg capsules, or VYNDAMAX 61 mg orally once-daily, taken as a single capsule. VYNDAMAX was developed for patient convenience; VYNDAQEL and VYNDAMAX are not substitutable on a per milligram basis.

“ATTR-CM is not only fatal, but also significantly underdiagnosed, with some patients cycling through multiple doctors and a myriad of tests over a period of years while the disease progresses,” said Isabelle Lousada, Founder and CEO, Amyloidosis Research Consortium. “ATTR-CM is a rare disease for which more education and awareness is needed. The approval of these medicines represents an important advance for patients; however, it is equally important that we work as a community to recognize the critical importance of early diagnosis.”

The FDA approval was based on data from the pivotal Phase 3 Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT), the first global, double-blind, randomized, placebo-controlled clinical study to investigate a pharmacological therapy for the treatment of this disease. In ATTR-ACT, VYNDAQEL significantly reduced the hierarchical combination of all-cause mortality and frequency of cardiovascular-related hospitalizations compared to placebo over a 30-month period (p=0.0006). Additionally, individual components of the primary analysis demonstrated a relative reduction in the risk of all-cause mortality and frequency of cardiovascular-related hospitalization of 30% (p=0.026) and 32% (p<0.0001), respectively, with VYNDAQEL versus placebo. Approximately 80% of total deaths were cardiovascular-related in both treatment groups. VYNDAQEL also had significant and consistent treatment effects compared to placebo on functional capacity and health status first observed at six months and continuing through 30 months. Specifically, VYNDAQEL reduced the decline in performance on the six-minute walk test (p<0.0001) and reduced the decline in health status as measured by the Kansas City Cardiomyopathy Questionnaire – Overall Summary score (p<0.0001). VYNDAQEL was well tolerated in this study, with an observed safety profile comparable to placebo. The frequency of adverse events in patients treated with VYNDAQEL was similar to placebo, and similar proportions of VYNDAQEL-treated patients and placebo-treated patients discontinued the study drug because of an adverse event.

Pfizer is committed to helping eligible ATTR-CM patients who have been prescribed VYNDAQEL or VYNDAMAX gain appropriate access. Pfizer supports patients by helping them understand their insurance coverage requirements and can connect eligible patients with financial assistance resources which may be available including the Pfizer Patient Assistance Program.*

About ATTR-CM
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a rare and fatal condition that is caused by destabilization of a transport protein called transthyretin, which is composed of four identical sub units (a tetramer). When unstable transthyretin tetramers dissociate, they result in misfolded proteins that aggregate into amyloid fibrils and deposit in the heart, causing the heart muscle to become stiff, eventually resulting in heart failure. There are two sub-types of ATTR-CM: hereditary, also known as variant, which is caused by a mutation in the transthyretin gene and can occur in people as early as their 50s and 60s; or with no mutation and associated with aging, known as the wild-type form, which is thought to be more common and usually affects men after age 60. Often ATTR-CM is diagnosed only after symptoms have become severe. Once diagnosed, the median life expectancy in patients with ATTR-CM, dependent on sub-type, is approximately two to 3.5 years.

About VYNDAQEL (tafamidis meglumine) and VYNDAMAX (tafamidis)
VYNDAQEL (tafamidis meglumine) and VYNDAMAX (tafamidis) are oral transthyretin stabilizers that selectively bind to transthyretin, stabilizing the tetramer of the transthyretin transport protein and slowing the formation of amyloid that causes ATTR-CM.

VYNDAMAX 61 mg is a once-daily oral capsule developed for patient convenience. VYNDAQEL and VYNDAMAX are not substitutable on a per milligram basis.

VYNDAQEL was granted Orphan Drug Designation for ATTR-CM in both the EU and U.S. in 2012 and in Japan in 2018. In June 2017 and May 2018, respectively, the FDA granted VYNDAQEL Fast Track and Breakthrough Therapy designations for ATTR-CM. In November 2018, the FDA granted Priority Review for the new drug application (NDA) for VYNDAQEL.

In March 2019, the Ministry of Labor Health and Welfare in Japan approved VYNDAQEL, under SAKIGAKE designation, for patients with wild-type and variant forms of ATTR-CM. Regulatory submissions for the use of VYNDAQEL in patients with ATTR-CM have been submitted to the European Medicines Agency (EMA) and are under review.

VYNDAQEL was first approved in 2011 in the EU for the treatment of transthyretin amyloid polyneuropathy (ATTR-PN), in adult patients with early-stage symptomatic polyneuropathy to delay peripheral neurologic impairment. ATTR-PN is a neurodegenerative form of amyloidosis that leads to sensory loss, pain and weakness in the lower limbs and impairment of the autonomic nervous system, Currently, it is approved for ATTR-PN in 40 countries, including Japan, countries in Europe, Brazil, Mexico, Argentina, Israel, Russia, and South Korea. VYNDAQEL and VYNDAMAX are not approved for the treatment of ATTR-PN in the U.S.

SOURCE

https://www.pfizer.com/news/press-release/press-release-detail/u_s_fda_approves_vyndaqel_and_vyndamax_for_use_in_patients_with_transthyretin_amyloid_cardiomyopathy_a_rare_and_fatal_disease

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Post TAVR: Management of conduction disturbances and number of valve recapture and/or repositioning attempts – Optimize self-expanding transcatheter aortic valve replacement (TAVR) positioning reduced the need for permanent pacemaker (PPM) implants down the road

Reporter: Aviva Lev-Ari, PhD, RN

  • The PPM rate dropped from 9.7% to 3.0% (P=0.035), according to a team led by Hasan Jilaihawi, MD, of NYU Langone Health in New York City.
  • the PARTNER 3 and CoreValve Low Risk trials in patients at low surgical risk showed PPM implant rates of 17.4% with the Evolut line, 6.6% with the balloon-expandable Sapien 3, and 4.1%-6.1% with surgery.

 

  • “The His bundle passes through the membranous septum, a few millimeters beneath the non-coronary/right coronary cusps. It is therefore not surprising that a deeper valve implantation increases the likelihood of mechanical damage of the His bundle leading to a transient or persistent conduction disturbance,” according to Rodés-Cabau.

To capture factors that contributed to need for PPM implantation, Jilaihawi and colleagues performed a detailed restrospective analysis on 248 consecutive Evolut recipients at Langone treated with the standard TAVR approach — aiming for 3-4 mm implant depth (in relation to the non-coronary cusp) and recapturing and repositioning when the device landed considerably lower. Patients with prior PPM implantation were excluded. Devices used were Medtronic’s Evolut R, Evolut Pro, and Evolut 34XL.

This analysis revealed that use of the large Evolut 34XL (OR 4.96, 95% CI 1.68-14.63) and implant depth exceeding membranous septum length (OR 8.04, 95% CI 2.58-25.04) were independent predictors of later PPM implantation.

From there, operators came up with the MIDAS technique and applied it prospectively to another 100 consecutive patients.

Besides bringing down the PPM implant rate to 3.0%, there were no more cases of valve embolization, dislocation, or need for a second valve.

The standard and MIDAS groups shared similar membranous septum lengths but diverged in average actual device depth, such that the standard group tended to have Evolut devices positioned deeper (3.3 mm vs 2.3 mm, P<0.001).

SOURCE

https://www.medpagetoday.com/cardiology/pci/81849

 

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