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Archive for the ‘Origins of Cardiovascular Disease’ Category


Precision Cardiology to Benefit from New Atlas of Cells of the Adult Human Heart

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

 

The Voice of Dr. Pearlman on potential clinical implications of the New Atlas:

 

Published on 9/24/2020 in Nature

Litviňuková, M., Talavera-López, C., Maatz, H. et al. Cells of the adult human heart. Nature (2020). https://doi.org/10.1038/s41586-020-2797-4

 

Abstract

Cardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and therapeutic strategies require deeper understanding of the healthy heart’s molecular processes. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavor. Here, using state-of-the-art analyses of large-scale single-cell and nuclei transcriptomes, we characterise six anatomical adult heart regions. Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes, and fibroblasts, revealing distinct atrial and ventricular subsets with diverse developmental origins and specialized properties. We define the complexity of the cardiac vasculature and its changes along the arterio-venous axis. In the immune compartment we identify cardiac resident macrophages with inflammatory and protective transcriptional signatures. Further, inference of cell-cell interactions highlight different macrophage-fibroblast-cardiomyocyte networks between atria and ventricles that are distinct from skeletal muscle. Our human cardiac cell atlas improves our understanding of the human heart and provides a healthy reference for future studies.

Author information

Affiliations

Corresponding authors

Correspondence to J. G. Seidman or Christine E. Seidman or Michela Noseda or Norbert Hubner or Sarah A. Teichmann.

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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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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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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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The role of PET/CT in diagnosing giant cell arteritis (GCA) and assessing the risk of ischemic events

 

Reporter: Aviva Lev-Ari, PhD, RN

 

 

May 20, 2019 — PET/CT images are offering evidence of a link between vascular patterns at the time of diagnosis for giant cell arteritis (GCA) and a patient’s risk of an ischemic event, Spanish researchers explained in a study published online on 12 May in the European Journal of Nuclear Medicine and Molecular Imaging.

The group found that patients with inflammation in vertebral arteries, which causes blood vessels to narrow, were five times more likely to develop ischemic symptoms. The information may be particularly helpful because GCA is difficult to diagnose in its early stages.

“Bearing in mind these results and our findings, we consider that the vertebral arteries should be carefully studied in patients with suspected GCA, not only to support the diagnosis but also to assess the risk of development of ischemic events,” wrote lead author Dr. Jaume Mestre-Torres and colleagues from Hospital Vall d’Hebron in Barcelona.

GCA’s challenges

Giant cell arteritis is an inflammatory disease that causes the large blood vessels to narrow and restrict blood flow. The affliction is typically seen in the temporal arteries and the aorta in adults older than 50. Currently, there is little information on how the disease develops, although there are indications that it may be linked to genetics.

The challenge for clinicians is that there are “no specific clinical symptoms that lead to the diagnosis of GCA, but headache and ischemic symptoms such as jaw claudication and transient visual loss or permanent visual loss may raise suspicion [of the disease],” the authors noted.

Results

In assessing visual loss, the team found no significant differences between patients with vertebral artery involvement and permanent visual loss (61.5%) and patients with vertebral artery issues and no permanent visual loss (58.8%) (p = 0.88). Interestingly, the presence of intrathoracic large-vessel vasculitis tended to protect against a patient’s likelihood of permanent visual loss.

In addition, “all patients with vertebral involvement but no aortic involvement showed ischemic manifestations at disease onset,” the researchers noted. “In contrast, none of the patients with aortic involvement but no vertebral hypermetabolism showed ischemic symptoms.”

SOURCE

https://www.auntminnieeurope.com/index.aspx?sec=sup&sub=mol&pag=dis&ItemID=617395

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@Cleveland Clinic – Serial measurements of high-sensitivity C-reactive protein (hsCRP) post acute coronary syndrome (ACS) may help identify patients at higher risk for morbidity and mortality

 

Reporter: Aviva Lev-Ari, PhD, RN

 

Original Investigation
March 6, 2019

Association of Initial and Serial C-Reactive Protein Levels With Adverse Cardiovascular Events and Death After Acute Coronary Syndrome, A Secondary Analysis of the VISTA-16 Trial

Key Points

Question  Are initial and serial increases in high-sensitivity C-reactive protein levels after acute coronary syndrome in medically optimized patients associated with increased risk of a major cardiac event, cardiovascular death, and all-cause death?

Findings  In this secondary analysis of the VISTA-16 randomized clinical trial that included 5145 patients, baseline and longitudinal high-sensitivity C-reactive protein levels were independently associated with increased risk of a major adverse cardiac event, cardiovascular death, and all-cause death during the 16-week follow-up.

Meaning  Monitoring high-sensitivity C-reactive protein levels in patients after acute coronary syndrome may help better identify patients at greater risk for recurrent cardiovascular events or death.

Abstract

Importance  Higher baseline high-sensitivity C-reactive protein (hsCRP) levels after an acute coronary syndrome (ACS) are associated with adverse cardiovascular outcomes. The usefulness of serial hsCRP measurements for risk stratifying patients after ACS is not well characterized.

Objective  To assess whether longitudinal increases in hsCRP measurements during the 16 weeks after ACS are independently associated with a greater risk of a major adverse cardiac event (MACE), all-cause death, and cardiovascular death.

Results  Among 4257 patients in this study, 3141 (73.8%) were men and the mean age was 60.3 years (interquartile range [IQR], 53.5-67.8 years). The median 16-week low-density lipoprotein cholesterol level was 64.9 mg/dL (IQR, 50.3-82.3 mg/dL), and the median hsCRP level was 2.4 mg/L (IQR, 1.1-5.2 mg/L). On multivariable analysis, higher baseline hsCRP level (hazard ratio [HR], 1.36 [95% CI, 1.13-1.63]; P = .001) and higher longitudinal hsCRP level (HR, 1.15 [95% CI, 1.09-1.21]; P < .001) were independently associated with MACE. Similar significant and independent associations were shown between baseline and longitudinal hsCRP levels and cardiovascular death (baseline: HR, 1.61 per SD [95% CI, 1.07-2.41], P = .02; longitudinal: HR, 1.26 per SD [95% CI, 1.19-1.34], P < .001) and between baseline and longitudinal hsCRP levels and all-cause death (baseline: HR, 1.58 per SD [95% CI, 1.07-2.35], P = .02; longitudinal: HR, 1.25 per SD [95% CI, 1.18-1.32], P < .001).

Conclusions and Relevance  Initial and subsequent increases in hsCRP levels during 16 weeks after ACS were associated with a greater risk of the combined MACE end point, cardiovascular death, and all-cause death despite established background therapies. Serial measurements of hsCRP during clinical follow-up after ACS may help to identify patients at higher risk for mortality and morbidity.

SOURCE

https://jamanetwork.com/journals/jamacardiology/fullarticle/2725734

 

Inflammation’s role in residual risk

Residual risk of cardiovascular events or death remains high following ACS, despite coronary revascularization and optimal guideline-directed treatment with antiplatelet and LDL cholesterol-lowering agents. Inflammation is thought to drive this risk, but no effective treatment for such inflammation is commercially available. The secretory phospholipase A2 inhibitor varespladib was developed to meet this need, and it was evaluated in VISTA-16.

VISTA-16 was an international, multicenter clinical trial that randomized 5,145 patients in a double-blind manner to varespladib or placebo on a background of atorvastatin treatment within 96 hours of presentation with ACS. The trial was terminated early due to futility and likely harm from the drug, which was subsequently pulled from development.

Implications for practice

The association of increasing CRP levels with residual cardiovascular risk may prompt more intensive treatment to lower this risk. In particular, a secondary analysis showed that use of antiplatelet agents (clopidogrel, ticlopidine and prasugrel) was associated with stable or decreasing hsCRP levels.

“Monitoring not only lipids but also hsCRP after ACS may help us better identify patients at increased risk for recurrent cardiovascular events or death,” notes Dr. Puri. “High or increasing CRP levels could be an indication to optimize dual antiplatelet therapy post-ACS, along with high-intensity statin therapy (and possibly PCSK9 inhibitors) and antihypertensive therapy, in addition to instituting measures that are globally beneficial, such as dietary modifications and cardiac rehabilitation/exercise.”

SOURCE

https://consultqd.clevelandclinic.org/increasing-inflammation-correlates-with-residual-risk-after-acute-coronary-syndrome/amp/?__twitter_impression=true

 

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

 

Biomarkers and risk factors for cardiovascular events, endothelial dysfunction, and thromboembolic complications

Larry H Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2014/09/09/biomarkers-and-risk-factors-for-cardiovascular-events-endothelial-dysfunction-and-thromboembolic-complications/

 

A Concise Review of Cardiovascular Biomarkers of Hypertension

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/04/25/a-concise-review-of-cardiovascular-biomarkers-of-hypertension/

 

Acute Coronary Syndrome (ACS): Strategies in Anticoagulant Selection: Diagnostics Approaches – Genetic Testing Aids vs. Biomarkers (Troponin types and BNP)

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/03/13/acute-coronary-syndrome-acs-strategies-in-anticoagulant-selection-diagnostics-approaches-genetic-testing-aids-vs-biomarkers-troponin-types-and-bnp/

 

In Europe, BigData@Heart aim to improve patient outcomes and reduce societal burden of atrial fibrillation (AF), heart failure (HF) and acute coronary syndrome (ACS).

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/07/10/in-europe-bigdataheart-aim-to-improve-patient-outcomes-and-reduce-societal-burden-of-atrial-fibrillation-af-heart-failure-hf-and-acute-coronary-syndrome-acs/

 

Cardiovascular Diseases and Pharmacological Therapy: Curations by Aviva Lev-Ari, PhD, RN, 2006 – 4/2018

https://pharmaceuticalintelligence.com/2014/04/17/cardiovascular-diseases-and-pharmacological-therapy-curations-by-aviva-lev-ari-phd-rn/

 

 

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Hypertriglyceridemia: Evaluation and Treatment Guideline

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Severe and very severe hypertriglyceridemia increase the risk for pancreatitis, whereas mild or moderate hypertriglyceridemia may be a risk factor for cardiovascular disease. Individuals found to have any elevation of fasting triglycerides should be evaluated for secondary causes of hyperlipidemia including endocrine conditions and medications. Patients with primary hypertriglyceridemia must be assessed for other cardiovascular risk factors, such as central obesity, hypertension, abnormalities of glucose metabolism, and liver dysfunction. The aim of this study was to develop clinical practice guidelines on hypertriglyceridemia.

The diagnosis of hypertriglyceridemia should be based on fasting levels, that mild and moderate hypertriglyceridemia (triglycerides of 150–999 mg/dl) be diagnosed to aid in the evaluation of cardiovascular risk, and that severe and very severe hypertriglyceridemia (triglycerides of >1000 mg/dl) be considered a risk for pancreatitis. The patients with hypertriglyceridemia must be evaluated for secondary causes of hyperlipidemia and that subjects with primary hypertriglyceridemia be evaluated for family history of dyslipidemia and cardiovascular disease.

The treatment goal in patients with moderate hypertriglyceridemia should be a non-high-density lipoprotein cholesterol level in agreement with National Cholesterol Education Program Adult Treatment Panel guidelines. The initial treatment should be lifestyle therapy; a combination of diet modification, physical activity and drug therapy may also be considered. In patients with severe or very severe hypertriglyceridemia, a fibrate can be used as a first-line agent for reduction of triglycerides in patients at risk for triglyceride-induced pancreatitis.

Three drug classes (fibrates, niacin, n-3 fatty acids) alone or in combination with statins may be considered as treatment options in patients with moderate to severe triglyceride levels. Statins are not be used as monotherapy for severe or very severe hypertriglyceridemia. However, statins may be useful for the treatment of moderate hypertriglyceridemia when indicated to modify cardiovascular risk.

 

References:

 

https://www.medpagetoday.com/clinical-connection/cardio-endo/77242?xid=NL_CardioEndoConnection_2019-01-21

https://www.ncbi.nlm.nih.gov/pubmed/19307519

https://www.ncbi.nlm.nih.gov/pubmed/23009776

https://www.ncbi.nlm.nih.gov/pubmed/6827992

https://www.ncbi.nlm.nih.gov/pubmed/22463676

https://www.ncbi.nlm.nih.gov/pubmed/17635890

 

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Paraoxonase 2 (PON2) appears to play a cardioprotective role in both human and experimental heart failure: Cardiologist Wai Hong Wilson Tang, MD, Director of Cleveland Clinic Lerner Research Institute’s Center for Clinical Genomics.

Reporter: Aviva Lev-Ari, PhD, RN

Enzyme Protects Heart Against Stress and Could Potentially Lead to New Heart Failure Treatments

https://consultqd.clevelandclinic.org/enzyme-protects-heart-against-stress-and-could-potentially-lead-to-new-heart-failure-treatments/amp/?__twitter_impression=true

Original Study:
 2018 Jun;121:117-126. doi: 10.1016/j.freeradbiomed.2018.04.583. Epub 2018 May 2.

Paraoxonase 2 prevents the development of heart failure.

Abstract

BACKGROUND:

Mitochondrial oxidation is a major source of reactive oxygen species (ROS) and mitochondrial dysfunction plays a central role in development of heart failure (HF). Paraoxonase 2 deficient (PON2-def) mitochondria are impaired in function. In this study, we tested whether PON2-def aggravates HF progression.

METHODS AND RESULTS:

Using qPCR, immunoblotting and lactonase activity assay, we demonstrate that PON2 activity was significantly decreased in failing hearts despite increased PON2 expression. To determine the cardiac-specific function of PON2, we performed heart transplantations in which PON2-def and wild type (WT) donor hearts were implanted into WT recipient mice. Beating scores of the donor hearts, assessed at 4 weeks post-transplantation, were significantly decreased in PON2-def hearts when compared to WT donor hearts. By using a transverse aortic constriction (TAC) model, we found PON2 deficiency significantly exacerbated left ventricular remodeling and cardiac fibrosis post-TAC. We further demonstrated PON2 deficiency significantly enhanced ROS generation in heart tissues post-TAC. ROS generation was measured through dihydroethidium (DHE) using high-pressure liquid chromatography (HPLC) with a fluorescent detector. By using neonatal cardiomyocytes treated with CoCl2 to mimic hypoxia, we found PON2 deficiency dramatically increased ROS generation in the cardiomyocytes upon CoCl2 treatment. In response to a short CoCl2 exposure, cell viability and succinate dehydrogenase (SDH) activity assessed by MTT assay were significantly diminished in PON2-def cardiomyocytes compared to those in WT cardiomyocytes. PON2-def cardiomyocytes also had lower baseline SDH activity. By using adult mouse cardiomyocytes and mitochondrial ToxGlo assay, we found impaired cellular ATP generation in PON2-def cells compared to that in WT cells, suggesting that PON2 is necessary for proper mitochondrial function.

CONCLUSION:

Our study suggests a cardioprotective role for PON2 in both experimental and human heart failure, which may be associated with the ability of PON2 to improve mitochondrial function and diminish ROS generation.

KEYWORDS:

Cardiomyopathy; Heart failure; Paraoxonase 2

PMID:
29729330
PMCID:
PMC5971153
 [Available on 2019-06-01]
DOI:
10.1016/j.freeradbiomed.2018.04.583

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