New research explores the earliest stages of coronary plaque inflammation

 Didn't your competent? doctor show you this video on how plaque forms and why cholesterol is not the problem?; INFLAMMATION IS! NO! So you DON'T have a functioning stroke doctor, do you? Why hasn't s/he been fired yet?

4 min. 36 seconds of explanation. This is what happened to my right carotid artery. My doctor should have explained this but no, he didn't say anything.

Inflammation In Atherosclerotic Plaque Formation   March 2013

The accent is a bit hard to understand and needs to be  rerecorded to a laypersons understanding. 

New research explores the earliest stages of coronary plaque inflammation

A Cedars-Sinai Health Sciences University-led study has identified molecular changes that appear to trigger atherosclerosis years before inflammation, sharing their findings in European Heart Journal.[1]

The group believes this could a key discovery in the development of next-generation early prevention therapies. 

The study's authors found previously unrecognized molecular pathways and a possible master regulator protein called MLXIPL that could become future targets for clinicians working to stop plaque from ever developing.

“We analyzed proteins and gene activity in coronary artery tissue from young adults who died of trauma and had no known coronary artery disease, and we found that more than half already had preclinical atherosclerosis,” first author Sarah Parker, PhD, an associate professor of cardiology and biomedical sciences and co-director of the proteomics and metabolomics core at Cedars-Sinai Health Sciences University, said in a statement. “This suggests that changes in cellular metabolism and communication begin before the inflammation long considered a hallmark of the disease.”

Parker said this research provides a direct picture of what is happening inside the artery wall and may explain why some people are more vulnerable to heart disease than others.There have been studies showing very early atheroma lesions appearing in the first decade of life. Even with that in mind, however, questions have remained. 

"What we haven’t understood is what causes those early changes to progress into dangerous plaques that lead to heart attacks," Parker explained. "In studying coronary artery tissue before people ever developed symptoms, we were able to capture some of the earliest molecular changes that appear to set the disease in motion."

She said a big surprise from this research is that there are cellular metabolism and communication changes before the development of the classic inflammatory signals usually associated with atherosclerosis. There has been a lot of research focused on addressing inflammation to prevent heart disease, but this takes things even further and may offer help identify new preventive therapies.

"What our study suggests is that important molecular changes begin much earlier," Parker said. "If we want to prevent plaque from forming, we need to understand those earliest changes—not just what happens after inflammation has already taken hold."

She explained that proteins can tell researchers how the body’s cells are responding to risk factors like cholesterol, blood pressure or smoking. The differences in protiens found in people's cells can help explain why people with identical cholesterol levels will result in one never having coronary disease, while the other develops plaques.

Signaling roles of sphingolipids in the ischemic brain and their potential utility as therapeutic targets

 But what about this problem with sphingolipids? Hasn't your competent? doctor initiated research to solve this? NO? So you DON'T have a functioning stroke doctor, do you?

Sphingolipids Contribute to Human Atherosclerotic Plaque Inflammation May 2016

The latest here:

Signaling roles of sphingolipids in the ischemic brain and their potential utility as therapeutic targets

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https://doi.org/10.1016/j.nbd.2024.106682

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open access

Highlights

• •
  Ischemic stroke leads to dysregulation of the sphingolipid metabolism.
• •
  Ceramide accumulation occurring post-stroke deteriorates injury and inhibiting its metabolizing enzymes enhances recovery.
• •
  S1P receptor modulation influences vascular function and immune cell trafficking post-stroke.
• •
  Sphingolipids are important for the formation and release of extracellular vesicles that stimulate brain remodeling.

Abstract

Sphingolipids comprise a class of lipids, which are composed of a sphingoid base backbone and are essential structural components of cell membranes. Beyond their role in maintaining cellular integrity, several sphingolipids are pivotally involved in signaling pathways controlling cell proliferation, differentiation, and death. The brain exhibits a particularly high concentration of sphingolipids and dysregulation of the sphingolipid metabolism due to ischemic injury is implicated in consecutive pathological events. Experimental stroke studies revealed that the stress sphingolipid ceramide accumulates in the ischemic brain post-stroke. Specifically, counteracting ceramide accumulation protects against ischemic damage and promotes brain remodeling, which translates into improved behavioral outcome. Sphingomyelin substantially influences cell membrane fluidity and thereby controls the release of extracellular vesicles, which are important vehicles in cellular communication. By modulating sphingomyelin content, these vesicles were shown to contribute to behavioral recovery in experimental stroke studies. Another important sphingolipid that influences stroke pathology is sphingosine-1-phosphate, which has been attributed a pro-angiogenic function, that is presumably mediated by its effect on endothelial function and/or immune cell trafficking. In experimental and clinical studies, sphingosine-1-phosphate receptor modulators allowed to modify clinically significant stroke recovery. Due to their pivotal roles in cell signaling, pharmacological compounds modulating sphingolipids, their enzymes or receptors hold promise as therapeutics in human stroke patients.

Keywords

Ceramide

Sphingomyelin

Sphingosine-1-phosphate

Ischemic stroke

1. Introduction

1.1. Functional roles of sphingolipids

Sphingolipids are enriched in cellular membranes, but their roles extend far beyond their function as mere structural elements. In comparison to other organs such as heart, spleen and liver, the concentration of the sphingolipids is particularly high in the brain and dysregulation of the sphingolipid metabolism is implicated in neurodegenerative disorders (Muralidharan et al., 2021; Piccinini et al., 2010).

Ceramide is structurally one of the simplest sphingolipid and is considered to be the most studied one. It consists of a sphingoid base, which is linked via an amide bond to a fatty acid (Alonso and Goni, 2018). Ceramide signaling is activated by several stress stimuli such as radiation, UV light or inflammatory cytokines like tumor necrosis factor (TNF) (Chatterjee and Wu, 2001; Martinez et al., 2012; Vit and Rosselli, 2003). Ceramide-rich platforms on cell membranes enable protein oligomerization in order to amplify transmembrane signaling (Stancevic and Kolesnick, 2010). These platforms are critically involved in apoptotic events. CD95 clustering on ceramide-rich platforms for instance precedes death-inducing signaling complex (DISC) formation and caspase activation (Grassme et al., 2003). In view of the importance of ceramide for pro-apoptotic pathways, pharmacological inhibition of ceramide formation was shown to increase cell survival under pathological conditions (Gulbins et al., 2013). More complex ceramide derivates such as galactosylceramide are essential components of myelin sheaths that insulate axons enabling fast transmission of electric impulses (Zoller et al., 2008). Galactosylceramide deficiency causes demyelination which consequently leads to severe impairment of motor coordination (Coetzee et al., 1996; Zoller et al., 2005), which again emphasizes the functional relevance of sphingolipids.

After binding to specific G protein-coupled receptors, bioactive sphingolipids such as sphingosine-1-phosphate (S1P) function as signaling molecules and stimulate the activation of complex cascades, which govern cellular processes such as cell migration and angiogenesis (Blaho and Hla, 2014). Treatment with S1P increases vascular density and further amplifies VEGF-induced angiogenesis (Lee et al., 1999a). S1P also stimulates the assembly of adherens junctions on endothelial cells by activating Rac/ Rho signaling (Lee et al., 1999a). Further, S1P has been attributed an anti-apoptotic effect (Lee et al., 1999a).

Sphingolipids are further implicated in cellular mechanisms that control the endocytic trafficking machinery. Release of exosomes can be reduced by inhibition of neutral sphingomyelinase (NSM)-mediated sphingomyelin hydrolysis using GW4869, spiroepoxide or glutathione (Trajkovic et al., 2008). Disturbed exosome release due to reduced ceramide likely occurs because ceramide-enriched domains facilitate the sorting of cargo destined for exosomal release into multivesicular bodies and inhibition of NSM substantially reduces the amount of specific cargo within the endosomal lumen (Trajkovic et al., 2008). Exosomes that are generated via this endosomal sorting complexes required for transport (ESCRT)-independent pathway typically exhibit a high ceramide content (Trajkovic et al., 2008). Moreover, hydrolysis of sphingomyelin leads to formation of early endocytic intermediates to which sphingosine kinase-1 is recruited, the enzyme that catalyzes phosphorylation of sphingosine to S1P (Shen et al., 2014). The importance of sphingosine kinase-1 for endosomal recycling is depicted by experiments showing that its knockdown causes accumulation of internalized transferrin, which is indicative for endosomal recycling defects (Shen et al., 2014). Further, sphingolipids may alter lysosomal function. Accumulation of unmetabolized sphingolipids results in severe pathological conditions as genetic deficiency of specific enzymes that regulate the sphingolipid metabolism are causative for lysosomal storage disorders that lead to dysfunctional lysosomes and impaired autophagic flux (Carsana et al., 2022; Platt et al., 2012). Niemann-Pick disease type-A, for example, is a severe neurodegenerative disorder associated with early childhood mortality and is caused by inherited acid sphingomyelinase (ASM) deficiency, which leads to accumulation of sphingomyelin in lysosomes (Horinouchi et al., 1995).

Given the importance of sphingolipids for pivotal cellular processes, this review aims to depict the signaling roles of prominent sphingolipids, namely ceramide, sphingomyelin and S1P, for pathological events following ischemic stroke. Another focus of this review is to outline how sphingolipids may serve as targets for potential therapeutic interventions.

 

More at link.

Atherosclerotic Plaque Disruption and Healing

If it ever occurs the final result of this research should provide interventions that make sure your plaque is the extinct version. What is your stroke hospital doing to ensure this research is followed up and creates protocols?

Atherosclerotic Plaque Disruption and Healing

As with geologists, cardiovascular researchers have long studied the mechanisms governing atherosclerotic plaque formation, disruption, and thrombosis (i.e. the ‘volcanoes’ eruption’), and the ascertained knowledge has guided our traditional approaches to atherosclerosis therapy. Yet the ability to predict plaque instability and the development of acute coronary syndrome (ACS) or sudden coronary death remains weak, suggesting that other potential pathogenic mechanisms should also be explored.²

In our review article recently published in the New England Journal of Medicine,³ we explored the hidden side of the moon: mechanisms of atherosclerotic plaque healing and their clinical and potential therapeutic implications. We know from historical pathology studies that healed plaques can be frequently found at the non-culprit coronary sites of patients dying from sudden cardiac death, and even in subjects dying from other causes.⁴ These plaques can be considered as ‘inactive volcanoes’ within the vasculature, either ‘extinct’ or ‘dormant’. By definition, an ‘extinct volcano’ is a volcano that has not erupted for at least 10 000 years and is not supposed to erupt again in the future, while a ‘dormant’ one is a volcano that is not erupting, but is expected to erupt again.¹

As with volcanoes, the healing process can either pacify the disrupted plaque so that it remains silent for the rest of the patient’s life, or instead, stabilize it for a variable time period before a new disruption occurs. Both pathology and in vivo imaging studies in fact suggest that atherosclerotic plaques may undergo multiple episodes of disruption and healing, and that accumulation of new granulation tissue may contribute to an increase in plaque burden and to progressive luminal narrowing.^4,5

Recent optical coherence tomography studies showed an association between the presence of healed coronary plaques and higher non-target lesion, ischaemia-driven revascularization rates, in the absence of acute events.⁶ These data confirm our original observation that patients with healed plaques are more likely to evolve towards a long-standing chronic coronary syndrome (CCS), while those without evidence of healed plaques more frequently experience a recurrence of ACS.⁵ These observations have led us to propose the ‘double hit’ theory of atherosclerosis as a possible explanation of the pathogenesis of ACS.^3,5,7 This is somewhat reminiscent of what happened in oncology where, after studying oncogenes for decades, it was discovered that half of all human cancers were prompted by a mutation in oncogene suppressor genes. In atherosclerosis, the first hit is the acute destabilization of an atherosclerotic plaque by either rupture or erosion, whereas the second hit is an impaired healing capacity.³

Why are these findings important for patients with ischaemic heart disease? Because they may help to better predict the natural history of coronary atherosclerosis and, most importantly, they may pave the way towards novel therapeutic strategies. While traditional therapies have focused almost exclusively on preventing atherosclerosis progression and on treating its acute thrombotic complications, new therapies may point strongly towards strategies of improving healing. Patients with an effective healing capacity seem to have more potent endogenous fibrinolytic and thrombolytic systems as well as polarization of inflammation towards a reparative phenotype, including the production of anti-inflammatory cytokines and the overexpression of alternative M2 macrophages.³

Therapeutic options might come from existing drugs as well as from novel agents. Intensive antithrombotic therapy has already proved effective in promoting healing of coronary plaque erosion,⁸ and the beneficial effects of aggressive lipid-lowering agents (e.g. high-dose statins, proprotein convertase subtilisin–kexin type 9 inhibitors) on plaque stabilization have been largely documented.³

Promising results may come from the use of anti-inflammatory agents, such as interleukin-1β antagonists (e.g. canakinumab) or low-dose colchicine.^9,10 Recently, low-dose colchicine has been demonstrated to significantly lower the risk of cardiovascular events in a randomized trial involving patients with CCS compared to placebo.¹⁰ Although the mechanisms behind this benefit have not been elucidated, they may be at least in part related to an improvement in a plaque healing capacity. Another intriguing approach may be the modulation of macrophage polarization towards a reparative phenotype through CD31-targeting molecules or epigenetic therapies, including DNA methylation, histone modifications, or modulation of microRNAs and long non-coding RNAs.³

In conclusion, although primary prevention and traditional therapies provide a key to stemming the worldwide spread of the atherosclerotic disease epidemic and its thrombotic complications, the recognition of the healing process as an active player, rather than an innocent bystander, in the pathogenesis of ischaemic heart disease may provide ground for novel treatment options. We must strive to move beyond the classic approach of focusing on the mechanisms of plaque instability only, and try to elucidate the hidden protective mechanisms, with the aim of converting ‘poor healers’ into ‘good healers’.

During the Second World War, Sir Winston Churchill stated: ‘Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning’. In the current era, we might be at the same turning point in the war against atherosclerosis. Promoting plaque healing in addition to preventing plaque disruption might considerably potentiate our armamentarium in the battle against cardiovascular diseases.

 

Raspberries improve postprandial glucose and acute and chronic inflammation in adults with type 2 diabetes

Is this the inflammation that causes plaque formation in atherosclerosis? A very simple question. Next questions; How much? Black or red?  Bad research if these aren't answered. What the hell were the mentors and senior researchers thinking? OR not thinking?

Raspberries improve postprandial glucose and acute and chronic inflammation in adults with type 2 diabetes

Annals of Nutrition and Metabolism — Schell J, et al. | February 15, 2019

In obese adults with type 2 diabetes, researchers studied the effects of daily dietary raspberries on postprandial and 4-week fasting glucose, lipids, and biomarkers of inflammation. This investigation was a randomized crossover study with two different phases: a postprandial phase of acute raspberry supplementation (2 separate days at least 1 week apart), followed by a 1-week washout phase, and then a 10-week diet supplement phase—with and without raspberry supplementation periods of 4 weeks each—separated by 2-week washout phase. After the raspberry vs control phase, the postprandial phase showed significantly lower levels of serum glucose at 2 and 4 hours postprandial. Furthermore, interleukin (IL)-6 and high-sensitivity tumor necrosis factor alpha (hsTNF-α) were lower in serum biomarkers of inflammation at 4 hours postprandial following raspberry vs control meal. In the raspberry vs control phase, postprandial serum triglycerides showed a declining trend at 4 hours. In adults with diabetes, dietary raspberries, which are low in calories and high in polyphenols and other nutrients, might reduce postprandial hyperglycemia and inflammation and generally have selected anti-inflammatory effects. There were no effects on fasting glucose and lipids, C-reactive protein, and arterial elasticity.

Read the full article on Annals of Nutrition and Metabolism

Nearly half of all US adults have CVD

And yet no discussion of inflammation. Without inflammation causing the plaque buildup the high blood pressure would likely be a minor problem. Just like high cholesterol is not really a problem if you have no inflammation. But then I'm not medically trained so I know nothing about this. 

Nearly half of all US adults have CVD

Benjamin EJ, et al. Circulation. 2019;doi:10.1161/CIR.0000000000000659.

January 31, 2019

Mariell Jessup

At least 48%, or 121.5 million, of all adults in the United States had some form of CVD from 2013 to 2016, according to the American Heart Association’s new Heart and Stroke Statistics.
The number of U.S. adults with CVD is an increase from previous years, which the authors of the report attribute to a change in the definition of hypertension after release of the 2017 AHA/American College of Cardiology guidelines.

See Also

• Nearly half of all US adults have CVD
• New guideline widens hypertension definition, incorporates CV risk
• Experts: Hypertension guideline sound, but implementation challenges ahead

“As one of the most common and dangerous risk factors for heart disease and stroke, this overwhelming presence of high blood pressure can’t be dismissed from the equation in our fight against cardiovascular disease,” AHA president Ivor J. Benjamin, MD, FAHA, director of the Cardiovascular Center at the Medical College of Wisconsin in Milwaukee, said in a press release. “Research has shown that eliminating high blood pressure could have a larger impact on CVD deaths than the elimination of all other risk factors among women and all except smoking among men.”
CVD deaths
CVD was the underlying cause of death for approximately one of every three deaths, or 840,678 deaths in the U.S. in 2016. CVD was the cause of more deaths annually compared with chronic lower respiratory disease and all forms of cancer combined, Emelia J. Benjamin, MD, ScM, FAHA, assistant provost for faculty development at Boston University School of Medicine and chair of the writing committee, and colleagues wrote.
CHD was the leading cause of CVD-related deaths in the U.S. in 2016 (43.2%), followed by stroke (16.9%), increased BP (9.8%), HF (9.3%), diseases of the arteries (3%) and other CVDs (17.7%).

At least 48%, or 121.5 million, of all adults in the United States had some form of CVD from 2013 to 2016, according to the American Heart Association’s new Heart and Stroke Statistics.

Source: Shutterstock

The leading global cause of death — CVD — accounted for more than 17.6 million deaths annually in 2016, which is expected to increase to more than 23.6 million by 2030, according to the report.
Heart disease, including hypertension, CHD and stroke, continues to be the No. 1 cause of death in the U.S., accounting for approximately 13% of deaths in 2016.
Data from 2005 to 2014 found that the estimated annual incidence of new MI was 605,000 and 200,000 for recurrent MIs. In addition, the average age at the first MI was 65.6 years for men and 72 years for women.
Approximately every 40 seconds, an adult in the U.S. will have an MI or stroke, according to the report. Stroke was the cause for approximately one of every 19 deaths in 2016. Among all causes of death, stroke ranked No. 5 when considered separately from other CVDs and killed approximately 142,000 people a year.

• 1
• 2

Perspective

Dariush Mozaffarian

These new findings highlight the crushing health and economic burdens of CVD and related obesity and type 2 diabetes. The economic consequences of CVD alone are seven times larger than the annual budgets of the NIH, CDC and FDA combined. These burdens are expected to double in the next 15 years.
Among different preventable causes, food and nutrition loom large. Robust strategies are urgently needed to rigorously incorporate nutrition into health care — a holistic “Food is Medicine” approach. This should include systematic changes in medical education and training by including more questions on nutrition, lifestyle and behavior change in the United States Medical Licensing Examination and specialty certifications; incorporation of nutrition and food security screening tools into electronic health record standards; changes to procurement standards for hospital cafeterias and patient food services; and use of mobile technologies to test innovative platforms for healthier eating that combine shared proximal goal setting, self-monitoring, peer support, regular feedback, gamification and financial incentives.
Goals and strategies of currently disconnected large federal programs, like SNAP and Medicare/Medicaid, which frequently cover the same individuals, should be integrated and harmonized. As providers move toward accountable care, risk-sharing payment models should invest in nutrition for meaningful cost-savings and improved patient outcomes. All these programs should include special focus on vulnerable and sensitive groups and address social determinants of health.
Today, 1 in 4 federal dollars and 1 in 5 dollars in the entire economy is spent on health care, largely on preventable diet-related diseases. This is entirely unsustainable. We are on a cliff, but falling over the edge so slowly and steadily that many don’t seem to notice. Food is Medicine offers a real chance at improving health, lowering disparities and reducing costs.

• Dariush Mozaffarian, MD, DrPH
• Dean
  Jean Mayer Professor of Nutrition
  Friedman School of Nutrition Science and Policy
  Tufts University, Boston
  Professor of Medicine, Division of Cardiology
  Tufts Medical School

Plaque Protrusion Tied to Stroke in Carotid Stenting

Be careful out there. For you and your stenting doctor to discuss. I still don't understand why you would medically need to stent a carotid artery at all if the Circle of Willis is complete. (Unless the whole point is revenue and profit generation) It would seem to make more sense to just close it up and prevent problems from there.  My right carotid artery has been closed for the past 10 years and I cognitively function quite well with no episodes of fainting. 

Plaque Protrusion Tied to Stroke in Carotid Stenting

Nearly 3% of carotid stenting procedures in a decade had plaque protrusion

• by Nicole Lou
  Reporter, MedPage Today/CRTonline.org April 18, 2017

Action Points

• Note that this observational study suggests that plaque protrusion during carotid stenting poses a high risk for subsequent stroke.
• Be aware that only 9 patients in this study had plaque protrusion, limiting the precision of estimates of effect.

Having plaque creep into the lumen of the stent during carotid artery stenting was strongly associated with ischemic strokes, researchers reported.
Over 10 years of carotid artery stenting, Japanese hospitals saw nine cases (a 2.6% rate) of plaque protrusion, wherein plaque is found inside the stent during the procedure. Plaque protrusion involved open-cell stents in all cases. The complication occurred with unstable plaque in 8 out of 9 cases.
Stroke occurred by 30 days in 6 of the 9 patients who had plaque protrusion (1 major stroke, 5 minor strokes). In addition, ischemic lesions were found in 8 of the 9 cases on the treated side at 48 hours on diffusion-weighted imaging, Masashi Kotsugi, MD, of Ishinkai Yao General Hospital in Japan, and colleagues reported in the April 24, 2017 issue of JACC: Cardiovascular Interventions.
Their study included 328 consecutive patients with carotid atherosclerotic stenoses who underwent stenting with IVUS from 2007 to 2016. Operators used embolic protection devices in all cases.
"The present results suggest that the protective effect of an embolic protection device against stroke may be limited in cases of plaque protrusion and may indicate it is not the embolic protection device but rather avoiding plaque protrusion that is necessary to prevent periprocedural ischemic stroke," Kotsugi's group suggested.
And to that end, they urged, "carotid artery stenting should be performed using a stent with as small a free cell area as possible to prevent plaque protrusion."
"Our recent strategy is as follows: if plaque protrusion occurs, we perform IVUS and then check large-volume plaque protrusion to determine if it is convex. In a case of convex plaque protrusion, we perform stent-in-stent placement using closed-cell stents until the plaque protrusion disappears. In a case of nonconvex plaque protrusion, we observe for 5 to 10 min, and, then, if the plaque protrusion is not changed, careful clinical follow-up is considered within 30 days after carotid artery stenting. If the plaque protrusion enlarges, stent-in-stent placement is performed until plaque protrusion disappears."
"When the findings from this study are paired with the emerging data on apparent reductions in both plaque protrusion on optical coherence tomography and new DW-MRI abnormalities with the use of mesh-covered stents, the case begins to grow for such improvements in stent design," commented William Gray, MD, of Lakenau Heart Institute in Wynnewood, Pa.
In an accompanying editorial, he continued: "Toward that end, a U.S. trial [SCAFFOLD] evaluating a mesh-covered open-cell stent in patients at high surgical risk has already completed enrollment ... and two other similar trials using different mesh technologies are imminent. Inherent in these technologies is the hope that the stent can be transformed from a potential offender into a reliable protector during carotid artery stenting. This advance, once proved, along with others such as direct carotid access for flow reversal and double-filtration strategies, will thereby continue to chisel away at the causes of stroke in carotid artery stenting to patients' benefit."
Good options with mesh technologies include the closed-cell Roadsaver (Terumo) and the open-cell C-guard (inspireMD): "Expectations for micromesh stents are high," according to the study authors.
Plaque protrusion was confirmed on both angiography and intravascular ultrasound (IVUS) in their study.
IVUS alone would have detected more cases of plaque protrusion (7.8%), Kotsugi's group found.
"The investigators pre-defined plaque protrusion as having to occur in both modalities, which cut by two-thirds the incidence of IVUS plaque protrusion and which will clearly affect many of the subsequent associations and conclusions," Gray commented.
Other caveats, according to the editorialist: the lack of a core lab, diffusion-weighted MRI not routinely performed before and after stenting, unblinded assessors, stent use not protocol-directed, lack of routine independent neurological assessment, treating plaque prolapse with a second stent, and the difficult distinction between plaque protrusion and actual thrombus.
The retrospective study was further limited by the 30-day follow-up and small sample size.

Kotsugi disclosed no conflicts of interest.
Gray reported consulting for Medtronic, Boston Scientific, Contego, WL Gore, and Silk Road Medical.

• Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner

• Primary Source

  JACC: Cardiovascular Interventions

  Source Reference: Kotsugi M, et al "Carotid artery stenting: investigation of plaque protrusion incidence and prognosis" JACC Cardiovasc Interv 2017; DOI: 10.1016/j.jcin.2017.01.029.

• Secondary Source

  JACC: Cardiovascular Interventions

  Source Reference: Gray WA "Blurred lines: assessing the stent as provocateur in carotid intervention" JACC Cardiovasc Interv 2017; DOI: 10.1016/j.jcin.2017.03.022.

Increase in noncalcified plaque associated with testosterone treatment in older men

Well your doctor has a lot of studying to do. 

Testosterone Improves Woman’s Brain Functions

FDA Concludes Testosterone Use May Increase Risk of Cardiovascular Events

 

FDA warns about blood clot risk with testosterone products

Testosterone increases neurotoxicity of glutamate in vitro and ischemia-reperfusion injury in an animal model

 

Thinking with your gonads: testosterone and cognition

 

Effect of testosterone on functional recovery in a castrate male rat stroke model

 

Lower Testosterone Levels Predict Incident Stroke and Transient Ischemic Attack in Older Men

 

Could androgens maintain specific domains of mental health in aging men by preserving hippocampal neurogenesis?

Single-Dose Testosterone Administration Impairs Cognitive Reflection in Men

The latest here:

Increase in noncalcified plaque associated with testosterone treatment in older men

Budoff MJ, et al. JAMA. 2017;doi:10.1001/jama.2016.21043.

February 21, 2017

Testosterone treatment in older men was linked to a significantly greater increase in coronary artery noncalcified plaque volume, according to a new study in JAMA.

See Also

• Testosterone therapy showed no increased risk for MI in older ...
• Higher levels of testosterone linked to lower stroke risk in ...
• Testosterone therapy increased risk for acute MI in some men

Featured

American Heart Association Scientific Sessions

• More Featured:

• Cardiometabolic Health Congress
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“Although testosterone replacement is increasingly being used clinically, the [CV] benefits and risk of testosterone administration to older men with age-related decline in testosterone levels remain uncertain,” Matthew J. Budoff, MD, professor of medicine at David Geffen School of Medicine at UCLA and program director and director of cardiac CT at Harbor-UCLA Medical Center, and colleagues wrote. “Several observational studies show an inverse association between serum testosterone concentration and adverse [CV] outcomes, the metabolic syndrome, diabetes, and mortality, independent of traditional [CV] risk factors.”
In a double blind, placebo-controlled trial, Budoff and colleagues analyzed 170 men aged 65 years or older with an average of two serum testosterone levels lower than 275 ng/dL and symptoms suggestive of hypogonadism. Participants were enrolled between June 2010 and June 2014 and were randomly assigned testosterone gel (n = 82) or placebo gel (n = 88) for 12 months.

Matthew J. Budoff

Of those enrolled, data were available for 138 participants (73 receiving intervention, 65 receiving placebo; mean age, 71 years; 81% white). At baseline, 50.7% participants (n = 70) had a coronary artery calcification (CAC) score higher than 300 Agatston units.
The primary outcome was noncalcified plaque volume and was determined by coronary CTA.
From baseline to 12 months, participants in the testosterone arm had a significantly greater increase in noncalcified plaque volume (from median value 204 mm³ to 232 mm³) compared with placebo (from median value 317 mm³ to 325 mm³) with an estimated difference of 41 mm³ (95% CI, 14-67; P = .003).
The median total plaque volume increased in the testosterone group from 272 mm³ to 318 mm³, compared with 499 mm³ to 541 mm³ for placebo (estimated difference, 47 mm³; 95% CI, 13-80; P = .006). The median CAC score decreased in in the testosterone group (from 255 to 244 Agatston units) and increased in the placebo group (from 494 to 503 Agatston units) from baseline to 12 months (estimated difference, –27 Agatston units; 95% CI, –80 to 26 Agatston units), according to the researchers.
No one in either group had a major adverse CV event.
“The increase in coronary artery noncalcified and total plaque volumes in men treated with testosterone is concerning because any limitation of the vascular lumen could be considered deleterious,” Budoff and colleagues wrote. “The clinical significance of these increases could depend on the differential effects of testosterone on the individual components of noncalcified plaque.”
The researchers concluded that larger studies are needed to understand the clinical implications. – by Cassie Homer

Laser-based camera improves view of the carotid artery

You'll have to ask your doctor if this is better at detecting possible problems than ultrasound or blood flow velocity in 4D.

Laser-based camera improves view of the carotid artery

University of Michigan Health System, 02/15/2017

Michigan Medicine researchers employ novel technology to monitor vulnerabilities for cardiovascular events, aid in diagnosis and treatment.
Strokes and heart attacks often strike without warning. But, a unique application of a medical camera could one day help physicians know who is at risk for a cardiovascular event by providing a better view of potential problem areas.

A new paper in the journal Nature Biomedical Engineering reports proof–of–concept results for this new imaging platform for atherosclerosis.

“The camera actually goes inside the vessels,” says first author Luis Savastano, MD, a Michigan Medicine resident neurosurgeon. “We can see with very high resolution the surface of the vessels and any lesions, such as a ruptured plaque, that could cause a stroke. This technology could possibly find the ‘smoking gun’ lesion in patients with strokes of unknown cause, and may even be able to show which silent, but at–risk, plaques may cause a cardiovascular event in the future.”

The scanning fiber endoscope, or SFE, used in the study was invented and developed by co–author and University of Washington mechanical engineering research professor Eric Seibel, PhD. He originally designed it for early cancer detection by clearly imaging cancer cells that are currently invisible with clinical endoscopes.

The Michigan Medicine team used the instrument for a new application: acquiring high–quality images of possible stroke–causing regions of the carotid artery that may not be detected with conventional radiological techniques. The team worked with senior author Thomas Wang, MD, PhD, who is at the forefront of novel imaging platforms. Wang is professor of internal medicine, biomedical engineering and mechanical engineering, and is the H Marvin Pollard Collegiate Professor of Endoscopy Research.

The team generated images of human arteries using the SFE, which illuminates tissues with multiple laser beams, and digitally reconstructs high–definition images to determine the severity of atherosclerosis and other qualities of the vessel wall.

“In addition to discovering the cause of the stroke, the endoscope can also assist neurosurgeons with therapeutic interventions by guiding stent placement, releasing drugs and biomaterials and helping with surgeries,” Seibel says.

In addition, the SFE uses fluorescence indicators to show key biological features associated with increased risk of stroke and heart attacks in the future.

“The ability to identify and monitor the biological markers that render a plaque unstable and at risk for rupture could enable the detection of individuals within high–risk populations who are most likely to suffer from cardiovascular events, and therefore benefit the most from preventive treatment during the asymptomatic stage,” says B. Gregory Thompson, MD, professor of neurosurgery at the University of Michigan Medical School and a senior author on the new paper.

“In addition, plaque–specific data could help physicians modulate treatment intensity of atherosclerosis, which is currently based on systemic surrogates such us cholesterol and blood sugar levels and occurrence of cardiovascular events such as stroke or myocardial infarction.”

All research is in the pre–clinical phase.

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Endogenous peptide inhibits atherosclerosis by reducing cholesterol levels

Can no one get out of this fixation on cholesterol?  You fucking idiots, cholesterol is not the problem, inflammation is, which grabs the cholesterol out of the bloodstream packing it into plaque.  Learn about cause and effect and stop trying to force statins to be the only solution. I actually want cholesterol since  approximately 25% of the total amount of the cholesterol present in humans is localized to the brain, most of it present in myelin.
How plaque forms: Bet your doctor doesn't explain this.
Inflammation In Atherosclerotic Plaque Formation  

http://www.news-medical.net/news/20170119/Endogenous-peptide-inhibits-atherosclerosis-by-reducing-cholesterol-levels.aspx 

Cells of the innate immune system that play an important role in development of atherosclerosis contain a protein that reduces levels of cholesterol in mice - and thus helps to inhibit or mitigate the disease.
Atherosclerosis remains one of the primary causes of premature death in modern Western societies. The term itself refers to insoluble, fat-rich deposits that form on the inner wall of major blood vessels resulting in a chronic, localized inflammation. These so-called plaques obstruct blood flow and can ultimately lead to heart attacks and strokes. The unresolved inflammatory reactions that lead to atherosclerosis are initiated by immune cells in response to perturbations in lipidmetabolism owing to the presence of excess cholesterol (hypercholesterolemia) in the circulation. Researchers led by LMU's Oliver Söhnlein have now shown in mice that one of the cell types involved produces a protein that inhibits atherosclerosis by intervening in cholesterol metabolism. The new finding, reported in the journal EBioMedicine, could open up new options for the treatment of atherosclerosis.
Initiation and progression of atherosclerosis are closely linked to the activation of specific classes of cells that are part of the immune system. In earlier experiments, Söhnlein and his colleagues had shown that white blood cells called neutrophils play an important role in the process. The most abundant protein found in human neutrophils is human neutrophil peptide 1 (HNP1), which is known to have anti-microbial and pro-inflammatory functions. In contrast, mouse neutrophils normally do not express this protein at all. "This observation provided us with a unique opportunity to study the function of this protein. To do so, we genetically constructed a mouse strain that is not only prone to atherosclerosis, but also produces high levels of HNP1," Söhnlein explains. Much to their surprise, the LMU team found that the atherosclerotic lesions that formed in these mice were much smaller than those seen in the mice that lacked HNP1. "We expected to see exactly the opposite effect - in particular because we had previously discovered that HNP1 stimulates the recruitment of atherosclerosis-promoting monocytes to sites of inflammation," Söhnlein adds.

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When they examined the HNP1-expressing mice more closely, the researchers discovered that the animals had lower levels of circulating cholesterol than control mice. Because cholesterol is not soluble in water, it is transported in the bloodstream in association with so-called lipoproteins. Lipoproteins are often divided into good guys and bad guys. The good guys, including HDL, transport cholesterol from the tissues to the liver and thus reduce the risk of atherosclerosis. The bad guys, like LDL, convey cholesterol in the opposite direction - from the liver to the tissues. High levels of circulating LDL thus enable more cholesterol to be delivered to endothelial cells that are especially prone to damage or are already damaged, and therefore tend to promote atherosclerosis. "Indeed, we were able to show that HNP1 binds to LDL in the bloodstream and induces rapid uptake of circulating LDL by the liver, thus reducing hypercholesterolemia," says Söhnlein. This can account for the reduction atherosclerotic lesions in HNP1-expressing mice.
The researchers believe that their findings may lead to new approaches to the treatment of hyperlipidemia. "Since HNP1 is a natural constituent of the human body, therapeutic use of the protein would be expected to be relatively free of side-effects and should not compromise immune defenses," Söhnlein points out.

Source:

http://www.en.uni-muenchen.de/news/newsarchiv/2017/soehnlein_hnp1.html

Effects of coconut oil on lipid accumulation in 3T3-L1 cells

Would this result in less deposits of arterial plaque? We'll never know. Don't do this on your own.
https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0036-1596845
J Rabalert¹, N Munkong¹, W Parklak¹, A Wongnopavich², P Hansakul³, N Lerdvuthisopon³

• ¹Graduate Studies, Faculty of Medicine, Thammasat University, Pathumthani 12120, Thailand
• ²Department of Biochemistry, Faculty of Medicine, Chiangmai University, Chiangmai 50100, Thailand
• ³Institue of Preclinical Science, Faculty of medicine, Thammasat University, Pathumthani 12120, Thailand

Further Information

• Congress Abstract
• Full Text

 

Consumption of medium-chain triglyceride as coconut (Cocos nucifera L., Arecaceae) oil was shown to reduce fat deposition both in human and animals [1, 2]. Since coconut oil (CO) consisted of 47% lauric acid (decanoate, LaA), mechanism of CO in comparison to LaA on fat deposition was verified in 3T3-L1 cells. Cell viability was assessed by tetrazolium/formazan assay. Density of Oil Red O stained material (OROSM) was observed. Both assays were expressed as % of control (1% ethanol and 1% dimethyl sulfoxide instead of CO and LaA, respectively). Relative gene expression of adipogenic nuclear factors, peroxisome proliferator activated receptor gamma (PPARγ) and CCAAT-enhancer-binding protein alpha (C/EBPα) were assessed by real-time quantitative PCR. The results showed that % cell viability was significantly (p < 0.05) lower than control when cells were treated with the highest dose of LaA (100 µg/mL) for 8 days indicating the potential toxicity. Both CO and LaA were significantly reduced mean ± SEM of the % OROSM density at day 8 (67.17 ± 4.40, 69.27 ± 3.89 and 74.66 ± 5.02 when cells were treated with 670, 1340 and 2012 µg CO/mL, respectively; 59.37 ± 3.22 and 65.96 ± 6.27 when cells were treated with 20 and 40 µg LaA/mL, respectively). Relative gene expressions were significantly reduced by both CO and LaA at day 8 (PPARγ: 0.54 ± 0.02 and 0.62 ± 0.02; C/EBPα: 0.37 ± 0.04 and 0.49 ± 0.09 when cells were treated with 670 and 1340 µg CO/mL or PPARγ: 0.38 ± 0.03 and 0.55 ± 0.03; C/EBPα: 0.49 ± 0.01 and 0.37 ± 0.03 when cells were treated with 20 and 40 µg LaA/mL, respectively). In conclusion, the medium-chain fatty acid both in CO and as LaA were able to reduce fat accumulation in adipocyte during its differentiation. It is worth, then, to study its effect on the ectopic fat deposition as well.
Acknowledgements: Two institutes were acknowledged for their funding: Research Unit, Faculty of Medicine, Thammasat University; Higher Education research Promotion and National Research Project of Thailand.
Keywords: Lauric acid, OROSM, PPARγ, C/EBPα.
References:
[1] Assunção ML, Ferreira HS, dos Santos AF. Effects of dietary coconut oil on the biochemical and anthropometric profiles of women presenting abdominal obesity. Lipids 2009; 44: 593 – 601
[2] Portillo MP, Serra F, Simon E, del Barrio AS, Palou A. Energy restriction with high-fat diet enriched with coconut oil gives higher UCP1 and lower white fat in rats. Int J Obesity 1998; 22: 974 – 979

Raising ‘good’ cholesterol doesn’t protect against heart disease after all, study finds

All because nobody went after the real cause of atherosclerosis, inflammation, cholesterol is just a side player in this. I wonder if anyone involved here even understands cause and effect. Don't discontinue your statins just because big pharma is making great profits selling drugs for the wrong cause.
How plaque forms: Bet your doctor doesn't explain this.
Inflammation In Atherosclerotic Plaque Formation  
 

New model of arterial thrombus formation is similar to popular video game
Maybe you want this to fix it.
Like maybe this plaque sander?

Analysis: Plaque 'Sander' Safety Durable

Raising ‘good’ cholesterol doesn’t protect against heart disease after all, study finds

“Good” cholesterol might be in for a name change.

Raising HDL, widely known as good cholesterol, for years has been thought to protect against heart attack and stroke. But a big new study published Monday found little evidence it does.

The finding upends the advice doctors have been giving millions of patients — and helps explain why the drug industry has failed time and again, despite billions in investment, to develop a drug that cuts deaths from heart disease by boosting HDL levels.

“When you explain [cholesterol levels] to patients, it’s very easy to say one number’s bad and the other number’s good,” said Dr. Dennis Ko, a cardiologist at Canada’s Institute for Clinical Evaluative Sciences and lead author of the study. But it turns out that HDL is associated with poor health generally and does not seem to affect cardiovascular risk.

In the study, Ko and his colleagues looked at years of data from about 630,000 people in Ontario, sorting their HDL scores from low to high. Those with basement-level HDL were more likely to die of cardiovascular complications, but the risk did not drop steadily as good cholesterol levels rose.

Instead, it dipped, then hit a plateau; people with HDL of about 40mg/dL had roughly the same risk as those with about 80 mg/dL. And death risks actually increased for those with extremely high levels of good cholesterol.
Further muddying the picture, people in the low-HDL group were also more likely to die of diseases unrelated to the heart. And they had lower incomes, higher body weights, and poorer diets than others in the study, all of which correlate with increased mortality on their own.
HDL has been thought to lower cardiovascular risk by cleansing the bloodstream of “bad” cholesterol and scrubbing the inner walls of blood vessels, so your levels of HDL were thought to predict your risk of heart attack or stroke. But this new data suggests HDL may just be a fatty substance along for the ride.
“It may be therefore that it’s reflecting other health habits that lead to greater risk, rather than actually being a risk factor itself,” said Dr. Steven Nissen, a Cleveland Clinic cardiologist not involved in the study.
The study, published in the Journal of the American College of Cardiology, will sound familiar to the drug industry, which has repeatedly failed to design a pill that might improve patients’ lives by increasing HDL.
A decade ago, Pfizer spent more than $800 million to get the HDL-boosting medication torcetrapib into late-stage trials, only to find that more patients died on the drug than on placebo. Roche was next to fail when its drug, dalcetrapib, came up short in a 16,000-patient trial in 2012. And last year, Eli Lilly shut down a study testing its evacetrapib on 12,000 patients after discovering that the drug had no effect on heart attack and stroke.
Those drugs, called CETP inhibitors, are meant to interrupt the process that turns HDL into LDL cholesterol, its “bad” relative. And, in a sense, they work — Lilly’s pill boosted HDL by about 130 percent and slashed LDL by more than one-third. But, time after time, changing that ratio of good to bad cholesterol has failed to improve outcomes for patients.

Despite the litany of disappointments, there’s one CETP pill still in the ring. Merck is in the final phase of a 30,000-patient study on anacetrapib, the last of the class in late-stage development. Results are expected early next year, but optimism does not abound.
“I have very little hope that the ongoing trial is going to work,” said Nissen, who chaired Lilly’s failed evacetrapib study. “And if you think about it, if that study also fails, what is the likelihood that anybody will do another large, Phase 3 trial? I think the answer is probably pretty low.”
Still, cardiologists said it may still be useful to keep measuring HDL in blood lipid tests, because it does seem to be correlated with other factors that can affect health, such as diet and exercise habits. Doctors can gather such information with questionnaires, but those are time-consuming and rely on patients accurately recounting their habits.
And HDL may yet redeem itself in the world of drug development. Good cholesterol is complex, with various particle sizes and subspecies floating around in the body. Ko and his colleagues applied a broad brush in their study, looking at HDL as a monolith. It’s possible a deeper look at HDL subtypes could reveal a more nuanced relationship with cardiovascular disease, Dr. Stephen Nicholls and Dr. Peter Psaltis wrote in an editorial accompanying the study.
And it’s possible that drugs to raise HDL may work only in people with certain genetic mutations.

Read More

New dietary guidelines tougher on meat, easier on cholesterol

Last year, mining the wreckage of Roche’s failed dalcetrapib study, researchers at the University of Montreal noted that the drug had a marked effect on a subset of patients with mutations to a gene called ADCY9. DalCor Pharmaceuticals, a UK startup, has raised $150 million in venture capital to see if Roche’s drug can have a second life as a targeted therapy.
“Our understanding of the HDL story has changed,” said Dr. Bassem Masri, a cardiovascular disease expert at Weill Cornell Medicine and NewYork-Presbyterian who helped run a slew of CETP trials. “It’s not just [about] increasing HDL; it might be that only a specific population will respond to that increase positively.”
Elsewhere, scientists are studying novel methods of boosting HDL, whether by stimulating other pathways in the body or injecting patients with synthetic good cholesterol. Considering past failures, it looks like an uphill battle. But anything’s possible.
“I’ve been doing medicine long enough that I’ve learned to say you never say never,” Nissen said.