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


COVID concern in Cardiology: Asymptomatic patients who have been previously infected demonstrating evidence on MRI of scarring or myocarditis

Reporters: Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

 

The Voice of Dr. Justin D. Pearlman, MD, PhD, FACC

Indeed, many viruses can cause inflammation and weakening of the heart.

So far there is no established action to take for prevention, and management is based on clinical manifestations of heart failure: shortness of breath, particularly if worse laying flat or worse with exertion, leg swelling (edema), blood tests showing elevated brain natriuretic peptide (BNP or proBNP, a marker of heart muscle strain), and a basic metabolic panel that may show “pre-renal azotemia” (elevation of BUN and Creatinine, typically in a ratio >20:1) and/or hyponatremia (sodium concentration below 135 mEq/dL). If any of the above are suspected, it is reasonable to get transthoracic echocardiography for systolic and diastolic function. If either systolic or diastolic function by ultrasound show significant impairment not improved by usual therapy (diuretic, ACEI/ARB/ARNI, blocker, aldosterone inhibitor e.g. spironolactone) then an MRI scar map may be considered (MRI scar maps show retention of gadolinium contrast agent by injured heart muscle, first demonstrated by Dr. Justin Pearlman during angiogenesis research MRI studies).

There is no controversy in the above, the controversy is a rush to expanded referral for cardiac MRI without clear clinical evidence of heart impairment, at a stage when there is no established therapy for possible detection of myocarditis (cardiac inflammation). General unproven measures for inflammation may include taking ginger and tumeric supplements if well tolerated by the stomach, drinking 2 cups/day of Rooibos Tea if well tolerated by the liver.

Canakinumab was recommended by one research group to treat inflammation and risk to the heart if the blood test hsCRP is elevated (in addition to potential weakening of muscle, inflammation activates complement, makes atherosclerosis lesions unstable, and thus may elevate risk of heart attack, stroke, renal failure or limb loss from blocked blood delivery). The canakinumab studies were published in NEJM and LANCET with claims of significant improvement in outcomes, but that was not approved by FDA or confirmed by other groups, even though it has biologic plausibility. https://www.thelancet.com/journals/lancet/article/PIIS0140-67361732247-X/fulltext

 

Some Heart Societies Agree on Cautions for COVID-Myocarditis Screening

— Official response has been modest, though

Such evidence of myocardial injury and inflammation on CMR turned up in a German study among people who recovered from largely mild or moderate cases of COVID-19 compared with healthy controls and risk factor-matched controls.

Then an Ohio State University study showed CMR findings suggestive of myocarditis in 15% of collegiate athletes after asymptomatic or mild SARS-CoV-2 infection.

But an open letter from some 50 medical professionals across disciplines emphasized that “prevalence, clinical significance and long-term implications” of such findings aren’t known. The letter called on the 18 professional societies to which it was sent on Tuesday to release clear guidance against CMR screening in the general population to look for post-COVID heart damage in the absence of symptoms.

The Society for Cardiac Magnetic Resonance quickly responded with a brief statement from its chief executive officer, Chiara Bucciarelli-Ducci, MD, PhD, agreeing that routine CMR in asymptomatic patients after COVID-19 “is currently not justified… and it should not be encouraged.”

She referred clinicians to the multisociety guidelines on clinical indications of CMR when deciding whether to scan COVID-19 patients. “While CMR is an excellent imaging tool for diagnosing myocarditis in patients with suspected disease, we do not recommend its use in patients without symptoms,” she added.

The American Heart Association didn’t put out any written statement but offered spokesperson Manesh Patel, MD, chair of its Diagnostic and Interventional Cath Committee.

“The American Heart Association’s position on this is that in general we agree that routine cardiac MRI should not be conducted unless in the course of a study” for COVID-19 patients, he said. “There’s a lot of evolving information around people with COVID, and certainly asymptomatic status, whether it’s recent or prior, it’s not clearly known what the MRI findings will mean or what the long-term implications are without both a control group and an understanding around population.”

The ACC opted against taking a stand. It provided MedPage Today with the following statement from ACC President Athena Poppas, MD:

“We appreciate the authors’ concerns about the potential mischaracterization of the long-term impact of myocarditis after a COVID-19 diagnosis and the need for well-designed clinical trials and careful, long term follow-up. The pandemic is requiring everyone make real-time decisions on how to best care for heart disease patients who may be impacted by COVID-19. The ACC is committed to helping synthesize and provide the most up-to-date, high quality information possible to the cardiovascular care team. We will continue to review and assess the scientific data surrounding cardiac health and COVID-19 and issue guidance to help our care team.”

While the open letter noted that some post-COVID patients have been asking for CMR, Walsh noted that primary care would likely see the brunt of any such influx. She personally has not had any patients ask to be screened.

SOURCE

https://www.medpagetoday.com/infectiousdisease/covid19/88704?xid=nl_covidupdate_2020-09-21

Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial

Summary

Background

Inflammation in the tumour microenvironment mediated by interleukin 1β is hypothesised to have a major role in cancer invasiveness, progression, and metastases. We did an additional analysis in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), a randomised trial of the role of interleukin-1β inhibition in atherosclerosis, with the aim of establishing whether inhibition of a major product of the Nod-like receptor protein 3 (NLRP3) inflammasome with canakinumab might alter cancer incidence.

Methods

We did a randomised, double-blind, placebo-controlled trial of canakinumab in 10 061 patients with atherosclerosis who had had a myocardial infarction, were free of previously diagnosed cancer, and had concentrations of high-sensitivity C-reactive protein (hsCRP) of 2 mg/L or greater. To assess dose–response effects, patients were randomly assigned by computer-generated codes to three canakinumab doses (50 mg, 150 mg, and 300 mg, subcutaneously every 3 months) or placebo. Participants were followed up for incident cancer diagnoses, which were adjudicated by an oncology endpoint committee masked to drug or dose allocation. Analysis was by intention to treat. The trial is registered with ClinicalTrials.govNCT01327846. The trial is closed (the last patient visit was in June, 2017).

Findings

Baseline concentrations of hsCRP (median 6·0 mg/L vs 4·2 mg/L; p<0·0001) and interleukin 6 (3·2 vs 2·6 ng/L; p<0·0001) were significantly higher among participants subsequently diagnosed with lung cancer than among those not diagnosed with cancer. During median follow-up of 3·7 years, compared with placebo, canakinumab was associated with dose-dependent reductions in concentrations of hsCRP of 26–41% and of interleukin 6 of 25–43% (p<0·0001 for all comparisons). Total cancer mortality (n=196) was significantly lower in the pooled canakinumab group than in the placebo group (p=0·0007 for trend across groups), but was significantly lower than placebo only in the 300 mg group individually (hazard ratio [HR] 0·49 [95% CI 0·31–0·75]; p=0·0009). Incident lung cancer (n=129) was significantly less frequent in the 150 mg (HR 0·61 [95% CI 0·39–0·97]; p=0·034) and 300 mg groups (HR 0·33 [95% CI 0·18–0·59]; p<0·0001; p<0·0001 for trend across groups). Lung cancer mortality was significantly less common in the canakinumab 300 mg group than in the placebo group (HR 0·23 [95% CI 0·10–0·54]; p=0·0002) and in the pooled canakinumab population than in the placebo group (p=0·0002 for trend across groups). Fatal infections or sepsis were significantly more common in the canakinumab groups than in the placebo group. All-cause mortality did not differ significantly between the canakinumab and placebo groups (HR 0·94 [95% CI 0·83–1·06]; p=0·31).

Interpretation

Our hypothesis-generating data suggest the possibility that anti-inflammatory therapy with canakinumab targeting the interleukin-1β innate immunity pathway could significantly reduce incident lung cancer and lung cancer mortality. Replication of these data in formal settings of cancer screening and treatment is required.

Funding

Novartis Pharmaceuticals.

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The Role of Cholesterol Crystals in increase of NLRP3 Inflammasome affecting Coronary Artery Disease & Carotid Atherosclerosis

Reporters: Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

The Voice of Dr. Justin D. Pearlman, MD, PhD, FACC

Justin D. Pearlman, MD, PhD, FACC – Scientific Expert & Key Opinion Leader on Cardiovascular Diseases, Cardiac Imaging & Complex Diagnosis in Cardiology: Senior Editor & Author

The study published in Lancet https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(20)30361-3/fulltext

shows plausible evidence for a sequence of events following atheroma crystal formation in blood vessel walls leading to inflammation and consequential injuries from atherosclerosis. The liquid crystal behavior of atheroma was first demonstrated in original PhD dissertation by JDPearlman MD PhD who demonstrated that 0.5 C temperature shift at body temperature converts the physical state of atheroma lipids to crystalline, known as liquid-crystal behavior, and studies he performed with NMR (nuclear magnetic resonance) and EPR (electron paramagnetic resonance) demonstrated that triglyceride levels impact the transition temperature. The current study shows a cascade of responses to the atheroma crystallization that leads to damaging inflammation and risk of acute obstruction. In particular, the current study demonstrates accumulation of blood complement factor complexes C1q and C5b-9, along with increases in complement receptors C5aR1, C5aR2 and C3aR1.  Priming human carotid plaques with C5a followed by cholesterol crystal incubation resulted in pronounced release of interleukins IL-1β, IL-18 and IL-1α. Further understanding of the dominant pathways linking atheroma crystallization to unstable plaque with clinical consequences (heart attack, stroke) points to additional opportunities for medication or gene therapy to mitigate the harm.

Cholesterol crystals use complement to increase NLRP3 signaling pathways in coronary and carotid atherosclerosis

Open AccessPublished:September 11, 2020 DOI:https://doi.org/10.1016/j.ebiom.2020.102985

Abstract

Background

During atherogenesis, cholesterol precipitates into cholesterol crystals (CC) in the vessel wall, which trigger plaque inflammation by activating the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome. We investigated the relationship between CC, complement and NLRP3 in patients with cardiovascular disease.

Methods

We analysed plasma, peripheral blood mononuclear cells (PBMC) and carotid plaques from patients with advanced atherosclerosis applying ELISAs, multiplex cytokine assay, qPCR, immunohistochemistry, and gene profiling.

Findings

Transcripts of interleukin (IL)-1beta(β) and NLRP3 were increased and correlated in PBMC from patients with acute coronary syndrome (ACS). Priming of these cells with complement factor 5a (C5a) and tumour necrosis factor (TNF) before incubation with CC resulted in increased IL-1β protein when compared to healthy controls. As opposed to healthy controls, systemic complement was significantly increased in patients with stable angina pectoris or ACS. In carotid plaques, complement C1q and C5b-9 complex accumulated around CC-clefts, and complement receptors C5aR1, C5aR2 and C3aR1 were higher in carotid plaques compared to control arteries. Priming human carotid plaques with C5a followed by CC incubation resulted in pronounced release of IL-1β, IL-18 and IL-1α. Additionally, mRNA profiling demonstrated that C5a and TNF priming followed by CC incubation upregulated plaque expression of NLRP3 inflammasome components.

Interpretation

We demonstrate that CC are important local- and systemic complement activators, and we reveal that the interaction between CC and complement could exert its effect by activating the NLRP3 inflammasome, thus promoting the progression of atherosclerosis.

Keywords

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Heart Failure in Women With Hypertensive Disorders of Pregnancy

Reporter: Aviva Lev-Ari, PhD, RN

 

Heart Failure in Women With Hypertensive Disorders of Pregnancy

Insights From the Cardiovascular Disease in Norway Project
Originally publishedhttps://doi.org/10.1161/HYPERTENSIONAHA.120.15654Hypertension. ;0

Hypertensive disorders of pregnancy (HDP) have been associated with heart failure (HF). It is unknown whether concurrent pregnancy complications (small-for-gestational-age or preterm delivery) or recurrent HDP modify HDP-associated HF risk. In this cohort study, we included Norwegian women with a first birth between 1980 and 2004. Follow-up occurred through 2009. Cox models examined gestational hypertension and preeclampsia in the first pregnancy as predictors of a composite of HF-related hospitalization or HF-related death, with assessment of effect modification by concurrent small-for-gestational-age or preterm delivery. Additional models were stratified by final parity (1 versus ≥2 births) and tested associations with recurrent HDP. Among 508 422 women, 565 experienced incident HF over a median 11.8 years of follow-up. After multivariable adjustment, gestational hypertension in the first birth was not significantly associated with HF (hazard ratio, 1.41 [95% CI, 0.84–2.35], P=0.19), whereas preeclampsia was associated with a hazard ratio of 2.00 (95% CI, 1.50–2.68, P<0.001). Among women with HDP, risks were not modified by concurrent small-for-gestational-age or preterm delivery (Pinteraction=0.42). Largest hazards of HF were observed in women whose only lifetime birth was complicated by preeclampsia and women with recurrent preeclampsia. HF risks were similar after excluding women with coronary artery disease. In summary, women with preeclampsia, especially those with one lifetime birth and those with recurrent preeclampsia, experienced increased HF risk compared to women without HDP. Further research is needed to clarify causal mechanisms.

SOURCE

https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.120.15654?utm_campaign=sciencenews20-21&utm_source=weekly-sn&utm_medium=email&utm_content=phd08-26-20&j=72055108&sfmc_sub=1648404797&l=7991033_HTML&u=633892723&mid=10171707&jb=0

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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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