{"product_id":"spence-recent-advances-in-pathogenesis-assessment-and-treatment-of-atherosclerosis","title":"Spence Recent advances in pathogenesis, assessment, and treatment of atherosclerosis","description":"\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eStandard therapy leaves 70-80% of cardiovascular risk remaining, but lifelong low LDL linked to an uncommon gene cut coronary risk by about 95%.\u003c\/li\u003e\n\u003cli\u003eIntestinal bacteria turn carnitine in red meat and phosphatidylcholine in egg yolk into TMAO, raising heart attack and stroke risk.\u003c\/li\u003e\n\u003cli\u003ePCSK9 inhibitors lower LDL and cardiovascular events by about 50%, even in statin-intolerant patients, but are currently very costly.\u003c\/li\u003e\n\u003cli\u003eMeasuring carotid plaque burden with ultrasound predicts risk better than intima-media thickness; highest plaque burden carried a 19.5% five-year risk.\u003c\/li\u003e\n\u003cli\u003eA 'treating arteries' strategy in high-risk patients reduced two-year stroke risk from 8.8% to 1%, but needs randomized trials.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\nRecent advances in the understanding and treatment of atherosclerosis (hardening of the arteries) are changing the way doctors prevent heart attacks and strokes. This 2016 review from Dr. J. David Spence at Western University's Stroke Prevention \u0026amp; Atherosclerosis Research Centre highlights three major breakthroughs: the discovery that intestinal bacteria convert certain foods into artery-damaging compounds, the arrival of powerful new cholesterol-lowering drugs called PCSK9 inhibitors, and advanced ultrasound techniques that can identify the 10-15% of patients with asymptomatic carotid stenosis who might genuinely benefit from surgery or stenting. The review also describes a bold \"treating arteries instead of risk factors\" strategy that cut the 2-year stroke risk in high-risk patients from 8.8% to 1%. For patients watching their cholesterol or managing vascular disease, these developments point toward a future of far more personalized and effective prevention.\n\n# Preventing Heart Attacks and Strokes: How New Research on Atherosclerosis Is Changing Patient Care\n\n## Table of Contents\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#background\"\u003eWhy This Research Matters\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#pathogenesis\"\u003eUnderstanding the Disease Process: How Plaque Forms\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#microbiome\"\u003eThe Gut Microbiome: How Intestinal Bacteria and Diet Interact\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#renal\"\u003eKidney Failure and the Microbiome: A Hidden Danger\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#pcsk9\"\u003ePCSK9 Inhibitors: A New Way to Lower LDL Cholesterol\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#treating-arteries\"\u003eTreating Arteries Instead of Risk Factors\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#carotid\"\u003eThe Debate Over Treating Asymptomatic Carotid Stenosis\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#plaque-burden\"\u003eWhy Measuring Carotid Plaque Burden Matters\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#tcd\"\u003eTranscranial Doppler Embolus Detection: Spotting Stroke Risk\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#plaque-characteristics\"\u003ePlaque Characteristics: What the Ultrasound Reveals\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#clinical-implications\"\u003eClinical Implications: What This Means for Patients\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations and Unanswered Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations for Patients\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n## \u003ch2 id=\"background\"\u003eWhy This Research Matters\u003c\/h2\u003e\nDespite decades of progress, standard therapy for atherosclerosis has been only partially effective. In most clinical trials, routine treatment with currently available medications reduced cardiovascular risk by only about \u003cstrong\u003e9-30%\u003c\/strong\u003e, leaving patients with a \u003cstrong\u003eresidual risk of 70-80%\u003c\/strong\u003e—meaning the majority of their risk remained despite treatment.\n\nThe stakes are enormous. Atherosclerosis, the buildup of plaque inside artery walls, is the underlying cause of most heart attacks and strokes. The review notes that a lifelong reduction of LDL cholesterol (\"bad\" cholesterol) resulting from a hereditary condition that keeps LDL naturally low leads to an approximately \u003cstrong\u003e95% reduction in coronary risk\u003c\/strong\u003e—suggesting that aggressively lowering cholesterol, if sustained over decades, could nearly eliminate heart attacks.\n\nLifestyle changes also pack a powerful punch. The US Health Professionals Study and the Nurses' Health Study found that people who adopted all five healthy lifestyle choices (not smoking, moderate alcohol intake, regular exercise, a healthy diet, and maintaining a healthy weight) achieved an \u003cstrong\u003e80% reduction in stroke\u003c\/strong\u003e. Swedish men with coronary artery disease who followed the same pattern also achieved an \u003cstrong\u003e80% reduction in recurrent heart attacks\u003c\/strong\u003e.\n\nThe way we eat matters enormously. The Cretan Mediterranean diet reduced cardiovascular events by \u003cstrong\u003e70% in secondary prevention\u003c\/strong\u003e (preventing a second event) and reduced stroke by nearly half in high-risk primary prevention (preventing the first event).\n\n## \u003ch2 id=\"pathogenesis\"\u003eUnderstanding the Disease Process: How Plaque Forms\u003c\/h2\u003e\nAtherosclerosis can be understood as a response to injury. Blood flow disturbances damage the endothelium—the delicate inner lining of the arteries. This triggers a cascade: platelets clump, macrophages (a type of white blood cell) penetrate into the artery wall, inflammation and oxidative stress ramp up, LDL becomes oxidized, and smooth muscle cells proliferate. The result resembles a scar forming inside the artery wall.\n\nTraditional risk factors identified in the famous Framingham Heart Study include hypertension, smoking, elevated LDL, diabetes, and left ventricular hypertrophy (essentially reflecting the long-term cumulative effect of blood pressure). But the importance of diet has been largely underappreciated, partly because statin drugs lower fasting LDL cholesterol and seemingly outweigh any effect of diet on fasting lipid levels.\n\nThat focus on fasting lipids is misplaced, the review argues. The key effects of diet occur during the post-prandial state—the hours after a meal. A high-fat, high-cholesterol meal increases arterial inflammation and oxidative stress and impairs endothelial function for several hours. Since most of the day is spent in this post-meal state, diet is far more important than fasting LDL alone would suggest.\n\n## \u003ch2 id=\"microbiome\"\u003eThe Gut Microbiome: How Intestinal Bacteria and Diet Interact\u003c\/h2\u003e\nOne of the most exciting recent discoveries is the role of the \u003cstrong\u003eintestinal microbiome\u003c\/strong\u003e—the trillions of bacteria living in our digestive tract—in cardiovascular disease. Hazen's group at the Cleveland Clinic found that dietary components are converted by intestinal bacteria into toxic compounds that aggravate atherosclerosis.\n\nThe two most important dietary culprits are:\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003ePhosphatidylcholine\u003c\/strong\u003e, found in egg yolk and other sources\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eCarnitine\u003c\/strong\u003e, found in animal flesh—with \u003cstrong\u003efour times as much\u003c\/strong\u003e in red meat as in fish or chicken\u003c\/li\u003e\n\u003c\/ul\u003e\n\nHere's how the damaging chain works: Intestinal bacteria convert these substances into \u003cstrong\u003etrimethylamine (TMA)\u003c\/strong\u003e—the compound that gives uremic breath its fishy odor. The liver then oxidizes TMA into \u003cstrong\u003etrimethylamine N-oxide (TMAO)\u003c\/strong\u003e, a substance that causes atherosclerosis in animal models. TMAO enhances the accumulation of cholesterol in macrophages, promotes foam cell formation in artery walls, and increases the risk of heart attack, stroke, and death.\n\nThe clinical evidence is striking. In patients undergoing coronary angiography, high levels of TMAO following a test dose of two hard-boiled eggs markedly increased risk. Patients in the top quartile of TMAO levels had a \u003cstrong\u003e2.5-fold increase\u003c\/strong\u003e in the 3-year risk of stroke, death, or myocardial infarction.\n\nRemarkably, the microbiome is modifiable. Vegans who consumed L-carnitine did \u003cem\u003enot\u003c\/em\u003e produce TMAO—because they lacked the intestinal bacteria that convert carnitine to TMA. This suggests that harmful bacteria could potentially be eradicated with antibiotics and replaced with beneficial bacteria through stool transplantation, an approach entirely analogous to the \"repoopulation\" treatment used for \u003cem\u003eClostridium difficile\u003c\/em\u003e infections. Dr. Spence reports that his own group is actively studying this possibility.\n\nThis may also help explain why the Mediterranean diet appears so beneficial: a diet rich in plant foods, fiber, and healthy fats likely supports a healthier gut bacterial community than a diet heavy in red meat and egg yolks.\n\n## \u003ch2 id=\"renal\"\u003eKidney Failure and the Microbiome: A Hidden Danger\u003c\/h2\u003e\nPatients with renal failure face cardiovascular risks that are dramatically higher than the general population. While elevated total homocysteine (tHcy) has long been suspected as a culprit, it accounts for only about \u003cstrong\u003e20% of the effect\u003c\/strong\u003e of impaired renal function on carotid plaque. Elevated levels of thiocyanate and asymmetric dimethylarginine (ADMA, a nitric oxide antagonist) further contribute, but these were known before.\n\nWhat's newly recognized is that the metabolic products of the intestinal microbiome are normally excreted in the urine. When kidneys fail, these toxins accumulate. Besides TMAO, other microbial products that likely contribute to cardiovascular risk in renal failure include:\n\u003cul\u003e\n\u003cli\u003e\u003cstrong\u003eIndoxyl sulfate\u003c\/strong\u003e\u003c\/li\u003e\n\u003cli\u003e\u003cstrong\u003eIndole-3-acetic acid\u003c\/strong\u003e\u003c\/li\u003e\n\u003cli\u003e\u003cstrong\u003ep-Cresyl sulfate\u003c\/strong\u003e\u003c\/li\u003e\n\u003cli\u003e\u003cstrong\u003ePhenylacetylglutamine\u003c\/strong\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\nFor patients at risk of cardiovascular disease, especially those with renal failure, the message is clear: limit intake of meat and egg yolk not only because of the high cholesterol content but also because of the carnitine in meat (particularly red meat) and the phosphatidylcholine in egg yolk.\n\n## \u003ch2 id=\"pcsk9\"\u003ePCSK9 Inhibitors: A New Way to Lower LDL Cholesterol\u003c\/h2\u003e\nStatins, which work by blocking the rate-limiting step in cholesterol synthesis (the enzyme HMG-CoA reductase), reduce fasting LDL and cardiovascular events. Their effectiveness is enhanced by combining them with ezetimibe, a drug that blocks cholesterol absorption in the intestine.\n\nBut many patients cannot tolerate statins. The review helps separate myth from reality:\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eMyths (not causally related effects):\u003c\/strong\u003e hepatotoxicity, nephrotoxicity, intracerebral hemorrhage, cataracts, and cognitive decline\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eTrue causally related adverse effects:\u003c\/strong\u003e myopathy (muscle damage) and a slightly increased risk of diabetes\u003c\/li\u003e\n\u003c\/ul\u003e\n\nThese real side effects likely stem from impairment of mitochondrial function caused by depletion of \u003cstrong\u003eubiquinone (coenzyme Q10)\u003c\/strong\u003e, which is essential for mitochondria—the energy-producing structures inside cells.\n\nAn entirely distinct approach recently became available: blocking the action of \u003cstrong\u003eproprotein convertase subtilisin-kexin type 9 (PCSK9)\u003c\/strong\u003e, an enzyme that breaks down LDL receptors. By preventing this breakdown, the number and duration of LDL receptors on cells increase, allowing more LDL to be cleared from the bloodstream. The result: both LDL and cardiovascular events are lowered by about \u003cstrong\u003e50%\u003c\/strong\u003e, even in patients who cannot tolerate statins.\n\nCurrent approaches to blocking PCSK9—monoclonal antibodies or RNA interference—are very effective but prohibitively costly. The review expresses hope that less expensive small-molecule drugs will be developed before long, which would make this revolutionary treatment widely accessible.\n\n## \u003ch2 id=\"treating-arteries\"\u003eTreating Arteries Instead of Risk Factors\u003c\/h2\u003e\nA fundamentally different paradigm is to treat the actual burden of atherosclerosis—the visible plaque in the arteries—rather than targeting intermediate risk factors such as blood pressure levels or LDL numbers. This approach was developed because treating patients according to then-current guidelines was \u003cstrong\u003efailing half of them\u003c\/strong\u003e: those patients had plaque progression and their risk was \u003cstrong\u003etwice\u003c\/strong\u003e that of patients with stable plaque or plaque regression, even after controlling for coronary risk factors.\n\nInitiated by Dr. Spence's group in 2003 and reported in 2010, the \"treating arteries\" approach produced dramatic results:\n\u003cul\u003e\n\u003cli\u003eHalved the proportion of patients with plaque progression (down to a quarter)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eDoubled\u003c\/strong\u003e the proportion with plaque regression (up to half)\u003c\/li\u003e\n\u003cli\u003eReduced microemboli on transcranial Doppler by \u003cstrong\u003ethree quarters\u003c\/strong\u003e\n\u003c\/li\u003e\n\u003cli\u003eReduced the very high risk of patients with asymptomatic carotid stenosis by \u003cstrong\u003eover 80%\u003c\/strong\u003e\n\u003c\/li\u003e\n\u003c\/ul\u003e\n\nThe specific numbers are remarkable: the 2-year risk of stroke fell from \u003cstrong\u003e8.8% to 1%\u003c\/strong\u003e, and the 2-year risk of myocardial infarction fell from \u003cstrong\u003e7.6% to 1%\u003c\/strong\u003e.\n\nEfforts are now underway to conduct randomized trials comparing usual care with the \"treating arteries\" approach, using measurement of \u003cstrong\u003e3D plaque volume\u003c\/strong\u003e—the most sensitive method available to assess how well therapies are working against the underlying disease.\n\n## \u003ch2 id=\"carotid\"\u003eThe Debate Over Treating Asymptomatic Carotid Stenosis\u003c\/h2\u003e\nCarotid stenosis is a narrowing of the main arteries in the neck that supply blood to the brain. Patients with severe \u003cem\u003esymptomatic\u003c\/em\u003e carotid stenosis (meaning they've already had a stroke or mini-stroke) clearly benefit from either carotid endarterectomy (CEA, surgical removal of plaque) or carotid artery stenting (CAS, insertion of a mesh tube to hold the artery open). However, the periprocedural risk of stroke or death with CAS is approximately \u003cstrong\u003etwice\u003c\/strong\u003e that with CEA.\n\nThe management of \u003cem\u003easymptomatic\u003c\/em\u003e carotid stenosis (narrowing found incidentally, without prior symptoms) is far more controversial. The risk of asymptomatic carotid stenosis with modern medical therapy has declined markedly in recent years, to about \u003cstrong\u003e0.5% per year\u003c\/strong\u003e. Some experts have even suggested that randomized trials in symptomatic stenosis should be repeated, comparing intervention against intensive medical therapy.\n\nThe statistics on current practice are startling:\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003e~90%\u003c\/strong\u003e of carotid interventions in the United States are performed for asymptomatic stenosis\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e~60%\u003c\/strong\u003e in Italy and Germany\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e~15%\u003c\/strong\u003e in Canada and Australia (which the author considers about right)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e0%\u003c\/strong\u003e in Denmark\u003c\/li\u003e\n\u003c\/ul\u003e\n\nEven though the most recent trials report that the risk of stroke or death with intervention—after deducting periprocedural risk—is similar to that with modern intensive medical therapy (about 0.5% per year), the total risk with intervention remains much higher once periprocedural complications are counted: \u003cstrong\u003e~3% with CAS and ~1.5% with CEA\u003c\/strong\u003e. There are also important caveats about higher risks in real-world practice, as opposed to results achieved by carefully vetted, highly experienced interventionalists in randomized trials.\n\nDr. Spence argues that these international discrepancies \"call into question not only the advisability but also the ethics\" of routine intervention for asymptomatic stenosis as practiced in the United States, noting that 90% of patients with asymptomatic carotid stenosis would be better treated with intensive medical therapy.\n\n## \u003ch2 id=\"plaque-burden\"\u003eWhy Measuring Carotid Plaque Burden Matters\u003c\/h2\u003e\nAlthough carotid intima-media thickness (IMT)—an ultrasound measurement of the inner two layers of the artery wall—is widely regarded as an indicator of \"preclinical atherosclerosis,\" it is actually a different phenotype that doesn't truly represent plaque. The measurement is complicated by two different approaches (with and without plaque thickness), and when plaque thickness is included, participants with and without plaque are often combined, which muddies the results.\n\nIt is increasingly clear that \u003cstrong\u003emeasuring carotid plaque burden is superior to measuring IMT\u003c\/strong\u003e, both for risk stratification and for assessing the effects of therapy. Plaque burden can be measured as:\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eTotal plaque area (TPA):\u003c\/strong\u003e the sum of the areas of all plaques seen in the extracranial carotid arteries, ranging from 0 to about \u003cstrong\u003e1200 mm²\u003c\/strong\u003e\n\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eTotal plaque volume (TPV):\u003c\/strong\u003e measured with 3D ultrasound\u003c\/li\u003e\n\u003c\/ul\u003e\n\nIMT has a very narrow dynamic range—only about \u003cstrong\u003e0.5 to 1.5 mm\u003c\/strong\u003e—which is a key reason it is a weak predictor of cardiovascular risk. The two-dimensional TPA and three-dimensional TPV ranges are far greater, offering much more room to detect meaningful changes.\n\nThe predictive power of TPA is compelling. After adjustment for age, sex, blood pressure, smoking, serum cholesterol, diabetes, homocysteine, and treatment of blood pressure and cholesterol, TPA strongly predicted risk among patients attending a vascular prevention clinic. The 5-year risk of stroke, death, or myocardial infarction by quartile of TPA was:\n\u003col\u003e\n\u003cli\u003e\n\u003cstrong\u003e5.6%\u003c\/strong\u003e (lowest quartile)\u003c\/li\u003e\n\u003cli\u003e\u003cstrong\u003e10.7%\u003c\/strong\u003e\u003c\/li\u003e\n\u003cli\u003e\u003cstrong\u003e13.9%\u003c\/strong\u003e\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e19.5%\u003c\/strong\u003e (highest quartile)\u003c\/li\u003e\n\u003c\/ol\u003e\n\nPlaque progression is equally ominous. Patients whose plaque progressed in the first year of follow-up had \u003cstrong\u003etwice the risk\u003c\/strong\u003e of those with stable plaque or regression. These findings were confirmed in a population-based study in Tromsø, Norway, where both heart attack and stroke were strongly predicted by TPA but not by IMT in the common carotid artery where there was no plaque.\n\nIMT also has a technical limitation: the annual change is only about \u003cstrong\u003e0.15 mm\u003c\/strong\u003e, while the resolution of the method is about \u003cstrong\u003e0.2-0.3 mm\u003c\/strong\u003e—meaning real changes are smaller than the measurement error. IMT progression does not predict risk, even in large populations, whereas progression of 3D plaque volume predicted cardiovascular events even in a small population. In the High Risk Plaque study, 3D plaque burden was highly correlated with coronary calcium (a marker of heart artery plaque), while IMT was not; plaque burden predicted cardiovascular risk to a similar extent as coronary calcium.\n\nFor patients without existing plaque, a more useful measurement is \u003cstrong\u003evessel wall volume\u003c\/strong\u003e—a 3D measurement of the intima-media layer that has a much greater dynamic range than IMT and, unlike IMT, is sensitive to the effects of therapy.\n\n## \u003ch2 id=\"tcd\"\u003eTranscranial Doppler Embolus Detection: Spotting Stroke Risk\u003c\/h2\u003e\nPerhaps the best validated method for identifying high-risk patients with asymptomatic carotid stenosis is \u003cstrong\u003etranscranial Doppler (TCD) embolus detection\u003c\/strong\u003e. This painless ultrasound technique monitors the blood flow in the brain's arteries and detects \u003cstrong\u003emicroemboli\u003c\/strong\u003e—tiny particles traveling to the brain that can break off from plaque in the carotid arteries and increase stroke risk.\n\nThe evidence is striking: patients with asymptomatic carotid stenosis who had \u003cstrong\u003etwo or more microemboli in 1 hour of monitoring\u003c\/strong\u003e had a 1-year stroke risk of \u003cstrong\u003e15.6%\u003c\/strong\u003e, indicating that they could indeed benefit from CEA or CAS.\n\nTCD embolus detection is remarkably accessible. The cost of a TCD machine is \u003cstrong\u003eless than the cost of two carotid stenting procedures\u003c\/strong\u003e, and training and certification in TCD embolus detection can be completed in a course of \u003cstrong\u003e3 or fewer days\u003c\/strong\u003e. The review argues that TCD embolus detection—or some other procedure to identify higher-risk patients—should be considered before patients undergo CAS or CEA for asymptomatic stenosis.\n\n## \u003ch2 id=\"plaque-characteristics\"\u003ePlaque Characteristics: What the Ultrasound Reveals\u003c\/h2\u003e\nBeyond plaque volume, certain characteristics of the plaque itself predict risk. In patients with asymptomatic carotid stenosis:\n\u003cul\u003e\n\u003cli\u003ePresence of \u003cstrong\u003ethree or more ulcers\u003c\/strong\u003e in either or both carotid arteries carried a risk similar to that of microemboli: an \u003cstrong\u003e18% 3-year risk of stroke or death\u003c\/strong\u003e\n\u003c\/li\u003e\n\u003cli\u003eThose with \u003cstrong\u003etwo or more microemboli\u003c\/strong\u003e had a \u003cstrong\u003e20% 3-year risk\u003c\/strong\u003e\n\u003c\/li\u003e\n\u003c\/ul\u003e\n\nCombining TCD embolus detection with detection of three or more ulcers increased the proportion of patients with asymptomatic stenosis who could benefit from intervention from \u003cstrong\u003e5% to 10%\u003c\/strong\u003e—a significant improvement in our ability to pick out those who need more than just medication.\n\nThe \u003cstrong\u003eAsymptomatic Carotid Emboli Study (ACES)\u003c\/strong\u003e confirmed the power of plaque characteristics to predict risk:\n\u003cul\u003e\n\u003cli\u003ePlaque echolucency (areas of plaque that appear dark on ultrasound, indicating soft, unstable material such as lipid or hemorrhage) at baseline increased the risk of ipsilateral stroke with a \u003cstrong\u003ehazard ratio (HR) of 6.43\u003c\/strong\u003e (95% confidence interval [CI] 1.36-30.44, P=0.019). This means patients with echolucent plaque had more than six times the stroke risk of those without it.\u003c\/li\u003e\n\u003cli\u003eA combination of plaque echolucency plus TCD microemboli markedly increased the risk of ipsilateral stroke: \u003cstrong\u003eHR 10.61\u003c\/strong\u003e (95% CI 2.98-37.82, P=0.0003). This association remained significant even after controlling for risk factors, degree of carotid stenosis, and antiplatelet medication.\u003c\/li\u003e\n\u003c\/ul\u003e\n\nOther plaque features under study include \u003cstrong\u003ejuxtaluminal black plaque\u003c\/strong\u003e—plaque or thrombus so echolucent (ultrasound-dark) that it can be seen only by observing a gap between the artery wall and the Doppler flow signal. Advanced \u003cstrong\u003eplaque texture analysis\u003c\/strong\u003e of ultrasound images is also being explored to identify dangerous plaque that may not yet show up as overt ulcers or echolucent material.\n\nFor context, a hazard ratio is a statistical measure of how much more likely one group is to experience an event compared with another group. A HR of 10.61 means the risk was more than ten times higher—an enormous increase that strongly suggests these patients should be considered for more aggressive therapy.\n\n## \u003ch2 id=\"clinical-implications\"\u003eClinical Implications: What This Means for Patients\u003c\/h2\u003e\nThis review carries several important messages for patients and their doctors:\n\n\u003cstrong\u003eRisk stratification is improving.\u003c\/strong\u003e Measuring carotid plaque burden is far more useful than traditional IMT for deciding who needs intensive therapy. Patients with high plaque burden or plaque progression on follow-up scans face two to three times the risk of those with stable or regressing plaque. For the 90% of patients with asymptomatic carotid stenosis who would be better treated with intensive medical therapy, modern imaging can now identify many of the 10-15% who would genuinely benefit from surgery or stenting.\n\n\u003cstrong\u003eDiet matters more than we thought.\u003c\/strong\u003e The discovery of the gut microbiome's role means that the carnitine content of red meat and the phosphatidylcholine in egg yolk contribute to cardiovascular risk through bacterial conversion to TMAO. This is especially critical for patients with renal failure, who cannot efficiently excrete these toxic metabolites.\n\n\u003cstrong\u003eNew drugs are on the horizon.\u003c\/strong\u003e PCSK9 inhibitors represent a powerful new way to lower LDL by 50% or more, though current costs are prohibitive. The hope of cheaper alternatives makes this a treatment to watch.\n\n\u003cstrong\u003eTreating the artery, not just the numbers, works.\u003c\/strong\u003e The \"treating arteries\" strategy produced dramatic reductions in stroke and heart attack risk—over 80%—in high-risk patients. This approach is now heading toward randomized trials.\n\n\u003cstrong\u003eThe ethics of intervention.\u003c\/strong\u003e The vast differences in how countries approach asymptomatic carotid stenosis raise serious questions about whether many invasive procedures are justified. Patients should understand that modern intensive medical therapy may be as good as—or better than—surgery or stenting for many asymptomatic patients.\n\n## \u003ch2 id=\"limitations\"\u003eLimitations and Unanswered Questions\u003c\/h2\u003e\nThis is a review article, not a randomized controlled trial, so it reflects the author's expert interpretation of the published literature rather than new patient data. Several important limitations deserve mention:\n\n\u003cul\u003e\n\u003cli\u003eThe \"treating arteries\" approach, while promising, needs confirmation in randomized trials before it becomes standard practice\u003c\/li\u003e\n\u003cli\u003eCurrent PCSK9 inhibitor strategies are prohibitively expensive, limiting access\u003c\/li\u003e\n\u003cli\u003eMicrobiome-based therapies (antibiotics, stool transplantation, or targeted elimination of harmful bacteria) are still under investigation and not yet ready for patient care\u003c\/li\u003e\n\u003cli\u003eThe review was based on research available as of 2016; the field has continued to evolve since that time\u003c\/li\u003e\n\u003cli\u003eDr. Spence's group has a financial interest in software for vascular risk reclassification based on carotid plaque burden, and he has received consulting and research support from multiple pharmaceutical companies, which should be considered when interpreting his recommendations about the value of plaque imaging\u003c\/li\u003e\n\u003c\/ul\u003e\n\n## \u003ch2 id=\"recommendations\"\u003eRecommendations for Patients\u003c\/h2\u003e\nBased on this research, here's what patients can reasonably consider discussing with their doctors:\n\n\u003col\u003e\n\u003cli\u003e\n\u003cstrong\u003eIf you already have atherosclerosis\u003c\/strong\u003e, or significant risk factors for it, ask whether a simple carotid ultrasound to measure plaque burden (TPA or TPV) would help clarify your true risk level. The 5-year risk range is wide—from 5.6% to 19.5% depending on plaque burden—and knowing where you stand can guide how intensively to treat.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eIf you've been told you have carotid stenosis\u003c\/strong\u003e found incidentally (asymptomatic), ask about transcranial Doppler embolus detection. If you have two or more microemboli in an hour of monitoring, your 1-year stroke risk is 15.6% and intervention may be worthwhile. If not, intensive medical therapy may be just as good—and far safer—than surgery or stenting.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eLimit red meat and egg yolk consumption\u003c\/strong\u003e, particularly if you have kidney disease. The gut bacteria convert carnitine and phosphatidylcholine into TMAO, which is linked to a 2.5-fold higher risk of stroke, death, or heart attack. This is true even if your fasting LDL cholesterol looks fine, because the damage happens in the post-meal state.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eFollow a Mediterranean-style diet\u003c\/strong\u003e, which has been shown to reduce cardiovascular events by 70% in secondary prevention and to cut stroke risk by nearly half in high-risk primary prevention.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eMake all the lifestyle changes that work.\u003c\/strong\u003e Not smoking, moderate alcohol intake, regular exercise, healthy diet, and maintaining a healthy weight together produced an 80% reduction in stroke and recurrent heart attack risk in large observational studies.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eIf you're unable to tolerate statins\u003c\/strong\u003e, ask about PCSK9 inhibitor therapy. While expensive, it lowers LDL and cardiovascular events by about 50%, and less costly alternatives are likely in development.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eIf a carotid intervention is being recommended for an asymptomatic stenosis\u003c\/strong\u003e, ask for a frank discussion of the periprocedural risks (about 1.5% with CEA and 3% with CAS in trials) versus the risk of modern intensive medical therapy (about 0.5% per year). In Denmark, no symptomatic carotid stenoses are routinely treated with intervention—consider getting a second opinion.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n## \u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat is the 'treating arteries' approach and how did it affect stroke risk?\u003c\/h3\u003e\n\u003cp\u003eInstead of only targeting risk factors such as LDL cholesterol or blood pressure, this approach directly treats the burden of plaque visible in the arteries. In one high-risk group, the two-year risk of stroke fell from 8.8% to 1% after this strategy was introduced in 2003 and reported in 2010.\u003c\/p\u003e\n\u003ch3\u003eWhat are PCSK9 inhibitors and who might benefit from them?\u003c\/h3\u003e\n\u003cp\u003eThese drugs block an enzyme that breaks down LDL receptors, allowing more LDL to be cleared from the blood. They lower LDL and cardiovascular events by about 50%, even in people who cannot tolerate statins. They are effective but currently very expensive, so cheaper alternatives are being developed.\u003c\/p\u003e\n\u003ch3\u003eHow can ultrasound help decide if carotid stenosis needs surgery or stenting?\u003c\/h3\u003e\n\u003cp\u003eCarotid plaque burden measured by ultrasound predicts five-year risk of stroke, death, or heart attack, ranging from 5.6% in the lowest quartile to 19.5% in the highest. Transcranial Doppler can also detect microemboli; two or more in one hour meant a 15.6% one-year stroke risk, suggesting intervention may help.\u003c\/p\u003e\n\u003ch3\u003eShould I limit red meat and egg yolks even if my cholesterol looks normal?\u003c\/h3\u003e\n\u003cp\u003eYes, according to this review. Gut bacteria turn carnitine in red meat and phosphatidylcholine in egg yolk into TMAO, which promotes artery plaque. This effect occurs after meals and may not show up in fasting LDL cholesterol. Limiting these foods is especially important for people with kidney disease.\u003c\/p\u003e\n\u003ch3\u003eWhat lifestyle changes reduce stroke and recurrent heart attack risk by 80%?\u003c\/h3\u003e\n\u003cp\u003eIn large observational studies, people who adopted all five healthy habits—not smoking, moderate alcohol intake, regular exercise, a healthy diet, and maintaining a healthy weight—achieved an 80% reduction in stroke and, in Swedish men with coronary disease, an 80% reduction in recurrent heart attacks.\u003c\/p\u003e\n\u003ch3\u003eIs surgery or stenting always needed for asymptomatic carotid stenosis?\u003c\/h3\u003e\n\u003cp\u003eNo. Modern intensive medical therapy lowers yearly stroke risk to about 0.5%, while intervention adds periprocedural risks—roughly 1.5% for carotid endarterectomy and 3% for stenting. About 90% of asymptomatic patients may be better treated with medication. Ask about transcranial Doppler embolus detection to identify higher-risk patients.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource\u003c\/h2\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47423008538780,"sku":null,"price":0.0,"currency_code":"DKK","in_stock":true}],"url":"https:\/\/diagnosticdetectives.dk\/products\/spence-recent-advances-in-pathogenesis-assessment-and-treatment-of-atherosclerosis","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}