Noncoronary Atherosclerosis Overview of Atherosclerosis

Updated: Dec 23, 2019
  • Author: F Brian Boudi, MD, FACP; Chief Editor: Yasmine S Ali, MD, FACC, FACP, MSCI  more...
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Overview of Atherosclerosis

Practice Essentials

Atherosclerosis is a disease of large and medium-sized muscular arteries and is characterized by endothelial dysfunction, vascular inflammation, and the buildup of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall. This buildup results in plaque formation, vascular remodeling, acute and chronic luminal obstruction, abnormalities of blood flow, and diminished oxygen supply to target organs.

Noncoronary atherosclerosis refers to atherosclerotic disease affecting large and medium-sized noncoronary arteries (eg, extracranial cerebrovascular disease, lower extremity occlusive disease, aneurysmal disease).

Signs and symptoms

The signs and symptoms of noncoronary atherosclerosis are highly variable. Patients with mild atherosclerosis may present with clinically important symptoms and signs of disease. However, many patients with anatomically advanced disease may have no symptoms and experience no functional impairment.

Signs and symptoms of noncoronary atherosclerosis that affect different organ systems include the following:

  • Central nervous system: Stroke, reversible ischemic neurologic deficit, transient ischemic attack

  • Peripheral vascular system: Intermittent claudication, impotence, nonhealing ulceration and infection of the extremities

  • Gastrointestinal (GI) vascular system: Mesenteric angina characterized by epigastric or periumbilical postprandial pain—may be associated with hematemesis, hematochezia, melena, diarrhea, nutritional deficiencies, and weight loss; abdominal aortic aneurysm that is typically asymptomatic (sometimes pulsatile) until the dramatic, and often fatal, signs and symptoms of rupture

  • Target organ failure: Occult or symptomatic visceral ischemia

Diagnosis

Examination findings of noncoronary atherosclerosis are highly variable but may provide objective evidence of extracellular lipid deposition, stenosis or dilatation of large muscular arteries, or target organ ischemia or infarction, such as the following:

  • Hyperlipidemia: Xanthelasma and tendon xanthomata

  • Cerebrovascular disease: Diminished carotid pulses, carotid artery bruits, and focal neurologic deficits

  • Peripheral vascular disease: Decreased peripheral pulses, peripheral arterial bruits, pallor, peripheral cyanosis, gangrene, and ulceration

  • Abdominal aortic aneurysm: Pulsatile abdominal mass, peripheral embolism, and circulatory collapse

  • Atheroembolism: Livedo reticularis, gangrene, cyanosis, ulceration, digital necrosis, GI bleeding, retinal ischemia, cerebral infarction, and renal failure

Laboratory testing

  • Lipid profile

  • Blood glucose and hemoglobin A1c

Imaging studies

  • Ultrasonography: For evaluating brachial artery reactivity and carotid artery intima-media thickness (measures of vessel wall function and anatomy, respectively) [1]

  • Intravascular ultrasonography: Generally considered the criterion standard for the anatomic study of the vessel wall (provides images of the thickness and the acoustic density of the vessel wall)

  • Magnetic resonance imaging: For noninvasive assessment of blood vessel wall structure and characterization of plaque composition

  • Nuclear perfusion imaging with single-photon emission computed tomography (SPECT) scanning or positron emission tomography (PET) scanning

Management

The prevention and treatment of atherosclerosis require risk factor control, including the medical management of hypertension, hyperlipidemia and dyslipidemia, diabetes mellitus, and cigarette habituation.

Pharmacotherapy

The following medications may be used in the management of noncoronary atherosclerosis:

  • HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme) reductase inhibitors (eg, pravastatin, simvastatin, lovastatin, fluvastatin, atorvastatin, rosuvastatin, pitavastatin)

  • Fibric acid derivatives (eg, fenofibrate, gemfibrozil)

  • Bile acid sequestrants (eg, cholestyramine, colestipol

  • Omega-3 polyunsaturated fatty acid

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Overview of Atherosclerosis

Atherosclerosis is a disease of large and medium-sized muscular arteries and is characterized by endothelial dysfunction, vascular inflammation, and the buildup of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall. This buildup results in plaque formation, vascular remodeling, acute and chronic luminal obstruction, abnormalities of blood flow, and diminished oxygen supply to target organs.

For patient education information, see Cholesterol Center and Brain & Nervous System Center, as well as High CholesterolCholesterol Charts (What the Numbers Mean), How to Lower Cholesterol, and Stroke.

See Coronary Artery Atherosclerosis for more information on this topic.

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Etiology of Atherosclerosis

The mechanisms of atherogenesis remain uncertain. An incompletely understood interaction exists between the critical cellular elements—endothelial cells, smooth muscle cells, platelets, and leucocytes—of the atherosclerotic lesion. Vasomotor function, the thrombogenicity of the blood vessel wall, the state of activation of the coagulation cascade, the fibrinolytic system, smooth muscle cell migration and proliferation, and cellular inflammation are complex and interrelated biologic processes that contribute to atherogenesis and the clinical manifestations of atherosclerosis.

The "response-to-injury" theory is most widely accepted explanation for atherogenesis. Endothelial injury causes vascular inflammation and a fibroproliferative response ensues. Probable causes of endothelial injury include oxidized low-density lipoprotein (LDL) cholesterol; infectious agents; toxins, including the byproducts of cigarette smoking; hyperglycemia; and hyperhomocystinemia.

Circulating monocytes infiltrate the intima of the vessel wall, and these tissue macrophages act as scavenger cells, taking up LDL cholesterol and forming the characteristic foam cell of early atherosclerosis. These activated macrophages produce numerous factors that are injurious to the endothelium.

Elevated serum levels of LDL cholesterol overwhelm the antioxidant properties of the healthy endothelium and result in abnormal endothelial metabolism of this lipid moiety. Oxidized LDL is capable of a wide range of toxic effects and cell/vessel wall dysfunctions that are characteristically and consistently associated with the development of atherosclerosis. These dysfunctions include impaired endothelium-dependent dilation and paradoxical vasoconstriction. These dysfunctions are the result of direct inactivation of nitric oxide by the excess production of free radicals, reduced transcription of nitric oxide synthase messenger ribonucleic acid (mRNA), and posttranscriptional destabilization of mRNA.

The decrease in the availability of nitric oxide also is associated with increased platelet adhesion, increased plasminogen activator inhibitor, decreased plasminogen activator, increased tissue factor, decreased thrombomodulin, and alterations in heparin sulfate proteoglycans. The consequences include a procoagulant milieu and enhanced platelet thrombus formation. Furthermore, oxidized LDL activates inflammatory processes at the level of gene transcription by up-regulation of nuclear factor kappa-B, expression of adhesion molecules, and recruitment of monocytes/macrophages.

The lesions of atherosclerosis do not occur in a random fashion. Hemodynamic factors interact with the activated vascular endothelium. Fluid shear stresses generated by blood flow influence the phenotype of the endothelial cells by modulation of gene expression and regulation of the activity of flow-sensitive proteins. Atherosclerotic plaques characteristically occur in regions of branching and marked curvature at areas of geometric irregularity and where blood undergoes sudden changes in velocity and direction of flow. Decreased shear stress and turbulence may promote atherogenesis at these important sites within the coronary arteries, the major branches of the thoracic and abdominal aorta, and the large conduit vessels of the lower extremities. (This article will focus on noncoronary sites of atherogenesis.)

One study suggested that hypercholesterolemia-induced neutrophilia develops in arteries primarily during early stages of atherosclerotic lesion formation. [2]

The earliest pathologic lesion of atherosclerosis is the fatty streak, which is the result of focal accumulation of serum lipoproteins within the intima of the vessel wall. Microscopy reveals lipid-laden macrophages, T lymphocytes, and smooth muscle cells in varying proportions.

The fatty streak may progress to form a fibrous plaque, the result of progressive lipid accumulation and the migration and proliferation of smooth muscle cells.

Platelet-derived growth factor, insulinlike growth factor, transforming growth factors alpha and beta, thrombin, and angiotensin II are potent mitogens that are produced by the activated platelets, macrophages, and dysfunctional endothelial cells that characterize early atherogenesis, vascular inflammation, and platelet-rich thrombosis at sites of endothelial disruption. The relative deficiency of endothelium-derived nitric oxide further potentiates this proliferative stage of plaque maturation.

The proliferating smooth muscle cells are responsible for the deposition of extracellular connective tissue matrix and form a fibrous cap that overlies a core of lipid-laden foam cells, extracellular lipid, and necrotic cellular debris. Growth of the fibrous plaque results in vascular remodeling, progressive luminal narrowing, blood-flow abnormalities, and compromised oxygen supply to the target organ.

Progressive luminal narrowing of an artery due to expansion of a fibrous plaque results in impairment of flow once more than 50-70% of the lumen diameter is obstructed. Flow impairment causes symptoms of inadequate blood supply to the target organ in the event of increased metabolic activity and oxygen demand.

Developing atherosclerotic plaques acquire their own microvascular network, which consists of a collection of vessels known as the vasa vasorum. These vessels are prone to hemorrhage and contribute to the progression of atherosclerosis. [3]

Denudation of the overlying endothelium or rupture of the protective fibrous cap may result in exposure of the thrombogenic contents of the core of the plaque to the circulating blood. This exposure constitutes an advanced or complicated lesion.

The plaque rupture occurs due to weakening of the fibrous cap. Inflammatory cells localize to the shoulder region of the vulnerable plaque. T lymphocytes elaborate interferon gamma, an important cytokine that impairs vascular smooth muscle cell proliferation and collagen synthesis. In addition, activated macrophages produce matrix metalloproteinases that degrade collagen. These mechanisms explain the predisposition to plaque rupture and highlight the role of inflammation in the genesis of the complications of the fibrous atheromatous plaque.

A plaque rupture may result in thrombus formation, partial or complete occlusion of the blood vessel, and progression of the atherosclerotic lesion due to organization of the thrombus and incorporation within the plaque.

Development of atherosclerosis from childhood through adulthood

The process of atherosclerosis begins in childhood with the development of fatty streaks. These lesions can be found in the aorta shortly after birth and appear in increasing numbers in persons aged 8-18 years. More advanced lesions begin to develop when individuals are aged approximately 25 years. Subsequently, an increasing prevalence of the advanced complicated lesions of atherosclerosis exists, and the organ-specific clinical manifestations of the disease increase with age through the fifth and sixth decades of life.

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Risk Factors for Atherosclerosis

A number of large epidemiologic studies in North America and Europe have identified numerous risk factors for the development and progression of atherosclerosis.

The risk factors can be divided into modifiable and nonmodifiable types and include hyperlipidemia, hypertension, cigarette habituation, diabetes mellitus, age, sex, physical inactivity, and obesity. In addition, a number of novel risk factors have been identified that add to the predictive value of the established risk factors and may prove to be a target for future medical interventions.

Hypertension

Hypertension has been shown, in epidemiologic and experimental studies, to accelerate atherosclerotic vascular disease and increase the incidence of clinical complications.

The mechanism by which hypertension causes these effects is not known, and some uncertainty exists as to what the primary and secondary factors are in a typically multifactorial syndrome. These factors may include the above-mentioned hyperlipidemia, hypertension, diabetes mellitus, obesity, and physical inactivity.

Hypertension is associated with morphologic alterations of the arterial intima and functional alterations of the endothelium that are similar to the changes observed in hypercholesterolemia and established atherosclerosis. Endothelial dysfunction is a feature of hypertension, hyperlipidemia, and atherosclerosis and is known to represent and contribute to the procoagulant, proinflammatory, and proliferative components of atherogenesis.

Diabetes mellitus

This is an important risk factor for hyperlipidemia and atherosclerosis and is commonly associated with hypertension, abnormalities of coagulation, platelet adhesion and aggregation, increased oxidative stress, and functional and anatomic abnormalities of the endothelium, and endothelial vasomotion.

Cigarette smoking

Cigarette smokers have double the risk for stroke compared with nonsmokers. [4]

C-reactive protein

In a cohort of healthy men, baseline C-reactive protein (CRP) levels were found to be predictive of symptomatic peripheral vascular disease. CRP reflects systemic inflammation, and these results support the hypothesis that chronic inflammation may play a role in the pathogenesis and progression of atherosclerosis.

Standardization of the CRP assay is required before this test may be clinically useful, and whether CRP levels are a truly modifiable risk factor remains unclear.

Metabolic syndrome

Metabolic syndrome is more common and elevated in association with risk factors for atherosclerosis, including elevated body mass index, lack of exercise, smoking, age, and diet.

Familial hypercholesterolemia

Familial hypercholesterolemia is an autosomal dominant disorder caused by a defect in the gene for the hepatic LDL receptor. In the United States, heterozygous familial hypercholesterolemia occurs in approximately 1 in 500 individuals. Homozygous familial hypercholesterolemia occurs in approximately 1 in 1 million individuals in the United States, and total cholesterol may exceed 1000 mg/dL.

Also see Risk Factors for Coronary Artery Disease.

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Epidemiology of Atherosclerosis

Rate of occurrence

The true frequency of atherosclerosis is difficult, if not impossible, to accurately determine, because it is a predominantly asymptomatic condition.

A study by Semba et al suggests that high concentrations of plasma klotho, a hormone that has been implicated in atherosclerosis, are independently associated with a lower likelihood of having CVD. [5]

Sex predilection

Atherosclerosis is more common in men than in women. The higher prevalence of atherosclerosis in men is thought to be due to the protective effects of female sex hormones. This effect is absent after menopause in women.

Age predilection

Most cases of atherosclerotic vascular disease become clinically apparent in patients aged 40 years or older.

Prognosis

The prognosis of atherosclerosis depends on a number of factors, including systemic burden of disease, the vascular bed(s) involved, and the degree of flow limitation. Wide variability exists, and clinicians appreciate that many patients with critical limitation of flow to vital organs may survive many years, despite a heavy burden of disease. (Conversely, myocardial infarction or sudden cardiac death may be the first clinical manifestation of atherosclerotic cardiovascular disease in a patient who is otherwise asymptomatic with minimal luminal stenosis and a light burden of disease.)

Much of this phenotypic variability is likely to be determined by the relative stability of the vascular plaque burden. Plaque rupture and exposure of the thrombogenic lipid core are critical events in the expression of the atherosclerotic disease process and determine the prognosis of atherosclerosis.

The ability to determine and quantify risk and prognosis in patients with atherosclerosis is limited by the inability to objectively measure plaque stability and other predictors of clinical events.

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Patient History

The symptoms of noncoronary atherosclerosis are highly variable. Patients with mild atherosclerosis may present with clinically important symptoms and signs of disease. However, many patients with anatomically advanced disease may have no symptoms and experience no functional impairment.

Although atherosclerosis was initially thought to be a chronic, slowly progressive, degenerative disease, it is now apparent that the disorder has periods of activity and quiescence. Although a systemic disease, atherosclerosis manifests in a focal manner and affects different organ systems in different patients for reasons that remain unclear.

Stroke, reversible ischemic neurologic deficit, and transient ischemic attack are manifestations of the impairment of the patient’s vascular supply to his or her central nervous system and are characterized by the sudden onset of a focal neurologic deficit of variable duration.

Peripheral vascular disease typically manifests as intermittent claudication, impotence, and nonhealing ulceration and infection of the extremities. Intermittent claudication describes calf, thigh, or buttock pain that is exacerbated by exercise and relieved by rest. Intermittent claudication may be accompanied by pallor of the extremity and paresthesias. (A patient with limb claudication can be assumed to have a significant atherosclerotic plaque burden in multiple vascular beds, including the coronary and cerebral vessels. In evaluating preoperative risk in such a patient, pay particular attention to careful risk stratification and medical or interventional efforts to reduce this risk.)

Visceral ischemia may be occult or symptomatic prior to the signs and symptoms of target organ failure.

Mesenteric angina is characterized by epigastric or periumbilical postprandial pain and may be associated with hematemesis, hematochezia, melena, diarrhea, nutritional deficiencies, and weight loss.

Abdominal aortic aneurysm typically is asymptomatic prior to the dramatic, and often fatal, symptoms and signs of rupture, although patients may describe a pulsatile abdominal mass.

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Physical Examination

As previously mentioned, the symptoms of noncoronary atherosclerosis are highly variable. Patients with mild atherosclerosis may present with clinically important disease signs and symptoms, while many patients with anatomically advanced disease display no symptoms and have no associated functional impairment.

The physical signs of noncoronary atherosclerosis provide objective evidence of extracellular lipid deposition, stenosis or dilatation of large muscular arteries, or target organ ischemia or infarction. These symptoms include the following:

  • Hyperlipidemia – Xanthelasma and tendon xanthomata

  • Cerebrovascular disease - Diminished carotid pulses, carotid artery bruits, and focal neurologic deficits

  • Peripheral vascular disease - Decreased peripheral pulses, peripheral arterial bruits, pallor, peripheral cyanosis, gangrene, and ulceration

  • Abdominal aortic aneurysm - Pulsatile abdominal mass, peripheral embolism, and circulatory collapse

  • Atheroembolism - Livedo reticularis, gangrene, cyanosis, ulceration, digital necrosis, gastrointestinal bleeding, retinal ischemia, cerebral infarction, and renal failure

The Copenhagen City Heart Study found that xanthelasmata (raised yellow patches around the eyelids) but not arcus corneae (white or grey rings around the cornea) constitutes an independent risk factor for cardiovascular disease. Presence of xanthelasmata indicated increased risk for myocardial infarction, ischemic heart disease, and severe atherosclerosis. [6]

With regard to atheroembolism, the presence of pedal pulses in the setting of peripheral ischemia suggests microvascular disease and includes cholesterol embolization.

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Lipid Profile

Elevated LDL cholesterol is a risk factor for atherosclerotic vascular disease. High triglycerides associated with low high-density lipoprotein (HDL) cholesterol—a pattern categorized as atherogenic dyslipidemia and often found in insulin resistance—are also a risk factor for vascular disease. 

The dal-PLAQUE trial tested the safety and efficacy of dalcetrapib, using novel noninvasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints. The results suggest that dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months; however, dalcetrapib may have potential beneficial vascular effects, including the reduction in total vessel enlargement over 24 months. The long-term safety and efficacy needs to be further investigated. [7]

Nicholls et al studied the efficacy and safety of cholesteryl ester transfer protein (CETP) inhibitors in combination with commonly used statins. They found that, compared with placebo or statin monotherapy, evacetrapib raised HDL-C and lowered LDL-C levels, with or without a statin drug. [8]

In an industry-supported study, patients with atherosclerotic cardiovascular disease and LDL-C levels of < 70 mg/dl (1.81 mol/L) experienced no incremental clinical benefit from the addition of niacin to statin therapy during a 36-month follow-up period, despite significant improvements in HDL-C and triglyceride levels. [9]

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Blood Glucose and Hemoglobin A1C

Routine measurement of blood glucose and hemoglobin A1c is appropriate in patients with diabetes mellitus. Measuring any number of parameters that may reflect inflammation, coagulation, fibrinolytic status, and platelet aggregability is possible. These measurements may prove to be valuable, but at this time, how these measurements affect clinical decision-making is unclear, and including them in routine clinical practice is premature.

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Ultrasonographic Examination

Ultrasonography aids in evaluating brachial artery reactivity and carotid artery intima-media thickness, which are measures of vessel wall function and anatomy, respectively. These evaluations remain research techniques at this time but hold promise as reliable, noninvasive (and therefore repeatable) measures of disease and surrogate end points for the evaluation of therapeutic interventions.

Brachial artery reactivity

The loss of endothelium-dependent vasodilation is a feature of even the early stages of atherosclerosis.

Flow-mediated dilation of the brachial artery has been pioneered as a means of evaluating the health and integrity of the endothelium. The healthy endothelium dilates in response to an increase in blood flow, whereas vessels affected by atherosclerosis do not dilate and may paradoxically constrict.

The availability of high-resolution ultrasonographic systems makes the visualization and measurement of small, peripheral conduit vessels, such as the human brachial artery, possible.

Carotid artery intima-media thickness

B-mode ultrasonography of the common and internal carotid arteries is a noninvasive measure of arterial wall anatomy that may be performed repeatedly and reliably in asymptomatic individuals. The combined thickness of the intima and media of the carotid artery is associated with the prevalence of cardiovascular risk factors and disease and an increased risk of myocardial infarction and stroke. This association is at least as strong as the associations observed with traditional risk factors.

Intravascular ultrasonography

Intravascular ultrasound (IVUS) is a catheter-based examination that provides images of the thickness and the acoustic density of the vessel wall. It has long been considered the criterion standard for the study of the anatomy of the vessel wall.

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MRI and Scintigraphy

Magnetic resonance imaging (MRI) may be used to gain information noninvasively about blood vessel wall structure and to characterize plaque composition. MRI of carotid plaque allows for the visualization of plaque composition and plaque components that have been associated with a higher risk of subsequent embolic events. Blood suppressed T1- and T2-weighted and proton density-weighted fast spin echo, gradient echo, and time-of-flight sequences are used to quantify plaque components. [10]

Nuclear perfusion imaging is performed with the use of single-photon emission computed tomography (SPECT) scanning or positron emission tomography (PET) scanning, which relies on the administration of radionuclide isotope that is accumulated by the targeted tissue.

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Treatment of Atherosclerosis

The prevention and treatment of atherosclerosis require risk factor control, including the medical treatment of hypertension, hyperlipidemia, diabetes mellitus, and cigarette habituation.

Some studies have claimed reversal of atherosclerosis with pharmacologic agents such as statins and cilostazol, but these need to be further tested before it can be determined whether they offer any significant benefit in reducing clinical events. [11]

Advances in the understanding of the vascular biology of atherosclerosis have raised the possibility of using novel therapies to address more directly the various aspects of endothelial dysfunction and the role of endothelial dysfunction in atherogenesis. Potential cellular targets include vascular smooth muscle cells, monocyte/macrophage cell lines, platelets, and endothelial cells. Evidence exists that antiplatelet agents, antioxidant therapies, amino acid supplementation, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers may prove to prevent or slow the progression of the disease.

Screening

Cardiovascular disease (CVD) risk factors associated with lifestyle include smoking, alcohol intake, diet, and exercise. Screening guidelines for modifiable lifestyle CVD risks in adults have been issued by the following organizations:

  • US Preventive Services Task Force (USPSTF)
  • American Heart Association (AHA)/American College of Cardiology (ACC)
  • European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS)

A comparison of the recommendations for diet, physical activity, and tobacco use screening and interventions are listed in Table 1, below.

Table. Screening and Intervention Recommendations for Diet, Physical Activity, and Tobacco Use (Open Table in a new window)

Adult Guidelines

Year

Risk Factor

Screening Populations

Recommended Interventions

US Preventive Services Task Force (USPSTF) [12]

2014

Diet and physical activity

Overweight or obese adults with additional cardiovascular risk

Intensive behavioral counseling interventions to promote a healthful diet and physical activity

USPSTF [13]

2012

Diet and physical activity

Adult without obesity who do not have known CVD risk factors

Primary care professionals should individualize the decision to offer or refer adults without obesity who do not have hypertension, dyslipidemia, abnormal blood glucose levels, or diabetes to behavioral counseling to promote a healthful diet and physical activity.

American Heart Association [14]

2010

Diet and physical activity

All adults

Clinicians should provide individual or group-based interventions to promote and maintain healthy diet and physical activity that include a combination of two or more of the following strategies:

  • Setting specific, proximal goals
  • Providing feedback on progress
  • Providing strategies for self-monitoring
  • Establishing a plan for frequency and duration of follow-up
  • Using motivational interviews
  • Building self-efficacy

European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) [15]

2012

Diet, physical activity, and tobacco use

All adults

Risk estimation for CVD using the Systematic COronary Risk Evaluation (SCORE)

 

All smokers offered assistance to quit

 

All patients encouraged to adopt healthy diet and increase physical activity

 

Multimodal behavioral interventions, integrating health education, physical exercise, and psychological therapy for psychosocial risk factors and coping with illness, should be prescribed for all patients with CVD

USPSTF [16]

2015

Tobacco Use

All adults

Ask all adults, including pregnant women, about tobacco use; advise those who use tobacco to stop using it, and provide behavioral interventions and US Food and Drug Administration-approved pharmacotherapy for smoking cessation.

Treatment of hypertension

The dietary and pharmacologic treatment of hypertension is associated with a decreased incidence of stroke.

See the Guidelines section for the classification and treatment of hypertension.

Management of hyperlipidemia and dyslipidemia

The 3-hydroxy-3-methyl Co-A (HMG-CoA) reductase inhibitors inhibit the rate-limiting step of cholesterol synthesis in the liver. They are effective in lowering the serum total cholesterol, LDL cholesterol, and triglyceride levels and in raising the serum HDL cholesterol level. HMG-CoA reductase inhibitors also have a low incidence of adverse effects, the most common being hepatotoxicity and myopathy.

The success of the HMG-CoA reductase inhibitors in reducing circulating lipid levels and improving the clinical and anatomic course of atherosclerosis has focused attention on the management of hyperlipidemia.

In addition, an important role remains for other hypolipidemic agents that may be of particular benefit for patients with refractory LDL hypercholesterolemia, hypertriglyceridemia, low HDL cholesterol, and elevated lipoprotein(a).

See the Guidelines section for management of cholesterol and dyslipidemia.

Management of diabetes mellitus

For patients with diabetes mellitus, strict control of comorbid risk factors is especially important. Ample evidence exists that such control reduces the incidence of the clinical complications of microvascular and macrovascular disease.

The benefit of strict glycemic control in the prevention of macrovascular disease has been difficult to confirm, although this intuitively is beneficial and is known to retard the progression of microvascular disease.

See the Guidelines section for CV risk reduction therapies in type 2 diabetes mellitus and CVD.

Treatment of familial hypercholesterolemia

Treatment options for familial hypercholesterolemia include combination drug therapy, although drug therapy alone often is inadequate because of the relative or absolute deficiency of hepatic LDL receptors.

Lipid apheresis is an effective means of reducing circulating lipid levels. Liver transplantation has been performed on young patients with severe disease.

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Drug Agents

HMG-CoA reductase inhibitors

These agents are competitive inhibitors of 3-hydroxy-3-methyl Co-A reductase, an enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis, resulting in up-regulation of LDL receptors in response to the decrease in intracellular cholesterol. The HMG-CoA reductase inhibitors are indicated for the secondary prevention of cardiovascular events and for the treatment of hypercholesterolemia and mixed dyslipidemia.

A number of HMG-CoA reductase inhibitors are indicated for patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments. One study suggests that the maximal doses of rosuvastatin and atorvastatin resulted in significant regression of coronary atherosclerosis. Although rosuvastatin resulted in lower LDL cholesterol levels and higher HDL cholesterol levels, a similar degree of regression of percent atheroma value (PAV) was observed in the two groups. [17] However, these agents may be less effective in patients with rare homozygous familial hypercholesterolemia, possibly because these patients are lacking functional LDL receptors, making it more likely to raise serum transaminases.

HMG-CoA reductase inhibitors include the following:

Fibric acid derivatives

The precise mechanism of action of this class of drugs is complex and incompletely understood. These agents increase the activity of lipoprotein lipase and enhance the catabolism of triglyceride-rich lipoproteins, which is responsible for an increase in the HDL cholesterol fraction.

A decrease in hepatic very low-density lipoprotein (VLDL) synthesis and an increase in cholesterol excretion into bile also appear to occur. The fibrates typically reduce triglyceride levels by 20-50% and increase HDL cholesterol levels by 10-15%. The decrease in VLDL and triglyceride levels results from the ability of fibric acid derivatives to enhance the synthesis of lipoprotein lipase.

The effect of fibric acid derivatives on LDL cholesterol is variable. Levels may be expected to decrease by 10-15%. In patients with marked hypertriglyceridemia, LDL cholesterol levels may increase, which likely reflects the ability of the LDL receptor to clear the increased LDL generated by increased VLDL catabolism.

Fibrate therapy may also be responsible for a decrease in the clotting ability of platelets and fibrinogen levels, which may account for some of the reported clinical benefits.

Fibric acid derivatives include fenofibrate (Tricor) and gemfibrozil (Lopid).

Bile acid sequestrants

The bile acid sequestrants block enterohepatic circulation of bile acids and increase the fecal loss of cholesterol. This results in a decrease in intrahepatic levels of cholesterol. The liver compensates by up-regulating hepatocyte LDL-receptor activity. The net effect is a 10-25% reduction in LDL cholesterol, but no consistent effect on triglycerides or HDL cholesterol exists.

Bile acid sequestrants include cholestyramine (Questran, LoCholest, Prevalite) and colestipol (Colestid).

Vitamin E (Vita-Plus E, Softgels, Aquasol E)

This antioxidant protects polyunsaturated fatty acids in membranes from attack by free radicals but is not seen to have a central role.

Omega-3 polyunsaturated fatty acid

The possible benefits of omega-3 polyunsaturated fatty acid in the treatment of atherosclerosis include effects on lipoprotein metabolism, hemostatic function, platelet/vessel wall interactions, antiarrhythmic actions, and the inhibition of proliferation of smooth muscle cells and therefore growth of the atherosclerotic plaque.

Fish oil feeding has also been found to result in moderate reductions in blood pressure and to modify vascular neuroeffector mechanisms.

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Guidelines

2019 ACC/AHA Prevention of CVD Guidelines

In September 2019, the American College of Cardiology (ACC) and the American Heart Association (AHA) published joint guidelines on the primary prevention of cardiovascular disease. [18]

It is recommended that atherosclerotic cardiovascular disease (ASCVD)–related risk factors be controlled via a team-based approach.

For adults, health-care visits should routinely include counseling on optimization of a physically active lifestyle.

At least 150 minutes per week of accumulated moderate-intensity or 75 minutes per week of vigorous-intensity aerobic physical activity (or an equivalent combination of moderate and vigorous activity) is recommended for ASCVD risk reduction in adults.

Improvement of the ASCVD risk factor profile through weight loss is recommended for patients with overweight or obesity.

It is recommended that adults with overweight or obesity achieve and maintain weight loss with the aid of counseling and comprehensive lifestyle interventions (including calorie restriction).

Improvement of glycemic control, achievement of weight loss (if necessary), and improvement of other ASCVD risk factors, via a tailored nutrition plan aimed at providing a heart-healthy dietary pattern, is recommended for all adults with type 2 diabetes mellitus (T2DM).

Improvement of glycemic control, achievement of weight loss (if necessary), and improvement of other ASCVD risk factors, via at least 150 minutes per week of moderate-intensity physical activity or 75 minutes of vigorous-intensity physical activity, is recommended for adults with T2DM.

If, as a result of a risk discussion, a decision is made to employ statin therapy, adults with high blood cholesterol with an intermediate ASCVD risk (≥7.5% to < 20% 10-year ASCVD risk) should be treated with a moderate-intensity statin.

In patients with high blood cholesterol who have an intermediate ASCVD risk (≥7.5% to < 20% 10-year ASCVD risk), reduction of low-density lipoprotein cholesterol (LDL-C) levels by at least 30% is recommended, while optimal ASCVD risk reduction can be targeted, particularly in high-risk patients (≥20% 10-year ASCVD risk), by reducing LDL-C levels by at least 50%.

Maximally tolerated statin therapy is recommended in patients aged 20-75 years with an LDL-C level of at least 190 mg/dL (≥4.9 mmol/L).

Among the nonpharmacologic interventions recommended for adults with elevated blood pressure (BP) or hypertension, including patients who need antihypertensive agents, are the following:

  • Weight loss

  • A heart-healthy dietary pattern

  • Sodium reduction

  • Dietary potassium supplementation

  • Increased physical activity with a structured exercise program

  • Limited alcohol

Primary prevention of cardiovascular disease (CVD) with BP-lowering medications is recommended for adults with an estimated 10-year ASCVD risk of at least 10% and an average systolic BP (SBP) of 130 mm Hg or higher or an average diastolic BP (DBP) of at least 80 mm Hg.

A BP target of below 130/80 mm Hg is recommended for adults with confirmed hypertension and a 10-year ASCVD event risk of at least 10%.

Treatment to a BP goal of below 130/80 mm Hg is recommended for adults with hypertension and chronic kidney disease.

Antihypertensive drug treatment should be administered to adults with T2DM and hypertension who have a BP of 130/80 mm Hg or higher, the aim being to reduce BP to below 130/80 mm Hg.

For adults, cessation of tobacco use should be facilitated by evaluation of such use at every health-care visit, with the status of a patient’s tobacco use recorded as a vital sign.

All adult tobacco users should be advised to quit.

In adult tobacco users, quit rates should be maximized by combining behavioral interventions with pharmacotherapy.

For more information, please go to Cardiovascular Disease Primary Prevention/Lifestyle Guidelines.

2019 ESC/EAS Dyslipidemia Guidelines

In August 2019, the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) released updates to their 2016 guidelines for the management of dyslipidemia. [19, 20] Among the changes are new and more aggressive proposed goals for low-density lipoprotein cholesterol (LDL-C) levels, revised cardiovascular (CV) risk stratification, particularly for patients at high to very high risk, as well as new patient management recommendations. [19, 20]  

New LDL targets across CV risk categories

For very-high-risk patients (10-year risk of CV death ≥10%): Use an LDL-C reduction of at least 50% from baseline and an LDL-C goal of below 1.4 mmol/L (< 55 mg/dL).

For very high-risk patients who experience a second vascular event within 2 years (not necessarily of the same type as the first event) while taking maximally tolerated statin therapy: An LDL-C goal of below 1.0 mmol/L (< 40 mg/dL) may be considered.

For patients at high risk (10-year risk for CV death of 5% to < 10%): Use an LDL-C reduction of at least 50% from baseline and an LDL-C goal of below 1.8 mmol/L (< 70 mg/dL).

For individuals at moderate risk (10-year risk for CV death of 1% to < 5%): Consider an LDL-C goal of below 2.6 mmol/L (< 100 mg/dL).

For individuals at low risk (10-year risk for CV death < 1%): Consider an LDL-C goal of below 3.0 mmol/L (< 116 mg/dL).

New recommendations

Cardiovascular imaging for assessment of ASCVD risk (should be considered)

Consider assessment of carotid and/or femoral arterial plaque burden on arterial ultrasonography as a risk modifier in individuals at low or moderate risk.

Consider coronary artery calcium (CAC) score assessment with computed tomography (CT) as a risk modifier in the CV risk assessment of asymptomatic individuals at low or moderate risk.

Lipid analyses for CVD risk estimation (should be considered)

Consider measurement of lipoprotein(a) (Lp(a)) at least once in each adult’s lifetime to identify those with very high inherited Lp(a) levels above 180 mg/dL (>430 nmol/L) who may have a lifetime risk of atherosclerotic CV disease (ASCVD) that is equivalent to the risk associated with heterozygous familial hypercholesterolemia (FH).

Pharmacotherapy of patients with hypertriglyceridemia (should be considered)

In high-risk (or above) patients with triglyceride (TG) levels between 1.5 and 5.6 mmol/L (135-499 mg/dL) despite statin treatment, consider the combination of n-3 polyunsaturated fatty acids (PUFAs) (icosapent ethyl 2 × 2g/day) with statins.

Treatment of patients with heterozygous FH (should be considered)

For primary prevention in individuals with FH at very-high risk, consider an LDL-C reduction of over 50% from baseline and an LDL-C goal below 1.4 mmol/L (< 55 mg/dL).

Dyslipidemia therapy in older patients

For primary prevention in older people aged up to 75 years, statin therapy is recommended based on the level of risk.

For primary prevention in older people older than 75 years, initiation of statin treatment may be considered if they are at high risk or above.

Dyslipidemia therapy in the setting of diabetes mellitus

For patients with type 2 diabetes mellitus (T2DM) at very-high risk, an LDL-C reduction of at least 50% from baseline and an LDL-C goal of below 1.4 mmol/L (< 55mg/dL) is recommended.

For those with T2DM at high risk, an LDL-C reduction of at least 50% from baseline and an LDL-C goal of below 1.8 mmol/L (< 70 mg/dL) is recommended.

For individuals with T1DM who are at high or very-high risk, statins are recommended.

Consider intensification of statin therapy before introducing combination therapy. If the goal is not reached, consider a statin combined with ezetimibe. (Each should be considered.)

Statin therapy is not recommended in premenopausal diabetic patients who are considering pregnancy or who are not using adequate contraception.

Lipid-lowering therapy in patients with ACS (should be considered)

For patients who present with an acute coronary syndrome (ACS), and whose LDL-C levels are not at goal despite already taking a maximally tolerated statin dose and ezetimibe, consider adding a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor early after the event (if possible, during hospitalization for the ACS event).

For more information, please go to Primary and Secondary Prevention of Coronary Artery DiseaseFamilial HypercholesterolemiaHypertriglyceridemia, and LDL Cholesterol Genetics.

2019 ACC Novel CV Risk Reduction Therapies in Type 2 Diabetes and CVD: Consensus Decision Pathways

The expert consensus decision pathways on the use of two major new classes of diabetes drugs—sodium-glucose cotransporter type 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs)—for cardiovascular (CV) risk reduction in patients with type 2 diabetes (TD2) and atherosclerotic CV disease (ASCVD) were released in November 2018 by the American College of Cardiology. [21, 22] The main focus of management is in the outpatient ambulatory setting.

The SGLT2 inhibitors appear to reduce major adverse CV events (MACE) and the risk of heart failure (HF) but increase the risk for genital mycotic infections, whereas GLP-1RAs offer reductions in MACE but are associated with transient nausea and vomiting. Both classes of agents have benefits in reducing blood pressure and weight, and they have a low risk for hypoglycemia.

For CV risk reduction, initiate agents with demonstrated CV benefit from either drug class at the lowest doses; no uptitration is necessary for SGLT2 inhibitors, whereas the GLP-1RAs should be slowly uptitrated (to avoid nausea) to the maximal tolerated dose.

At the initiation of an SGLT2 inhibitor or a GLP-1RA agent, clinicians should avoid hypoglycemia in patients by monitoring those with A1C levels near or below target, particularly when patients' existing diabetes therapies include sulfonylureas, glinides, or insulin.

In addition to reducing MACE and CV death, SGLT2 inhibitors are also suitable for preventing hospitalization for HF.

Empagliflozin is the preferred SGLT2 inhibitor based on the available evidence and overall benefit-risk balance.

Liraglutide should be the preferred agent among the GLP-1RAs for CV event risk reduction.

Two SGLT2 inhibitors (ie, canagliflozin, ertugliflozin) appear to be associated with an increased risk of amputation. It is unclear whether or not this is a class effect; therefore, clinicians should closely monitor patients on these agents who have a history of amputation, peripheral arterial disease, neuropathy, or diabetic foot ulcers.

Patients with T2D and clinical ASCVD on metformin therapy (or in whom metformin is contraindicated or not tolerated) should have an SGLT2 inhibitor or GLP-1RA with proven CV benefit added to their treatment regimen. For patients not on background metformin therapy, practitioners may use their clinical judgment to prescribe an SGLT2 inhibitor or GLP-1RA for CV risk reduction.

It appears reasonable to concomitantly use an SGLT2 inhibitor and a GLP-1RA with demonstrated CV benefit if clinically indicated, although such combination therapy has not been studied for CVD risk reduction.

For more information, please go to Coronary Artery Atherosclerosis.

2018 ACC/AHA Cholesterol Management Guidelines

The recommendations on management of blood cholesterol were released in November 2018 by the ACC, AHA, and multiple other medical societies. [23, 24]

The guideline's top 10 key recommendations for reducing the risk of atherosclerotic cardiovascular disease through cholesterol management are summarized below.

Emphasize a heart-healthy lifestyle across the life course of all individuals.

In patients with clinical atherosclerotic cardiovascular disease (ASCVD), reduce low-density lipoprotein cholesterol (LDL-C) levels with high-intensity statin therapy or the maximally tolerated statin therapy.

In individuals with very high-risk ASCVD, use an LDL-C threshold of 70 mg/dL (1.8 mmol/L) to consider the addition of nonstatins to statin therapy.

In patients with severe primary hypercholesterolemia (LDL-C level ≥190 mg/dL [≥4.9 mmol/L]), without calculating the 10-year ASCVD risk, begin high-intensity statin therapy.

In patients 40 to 75 years of age with diabetes mellitus and an LDL-C level of ≥70 mg/dL: Start moderate-intensity statin therapy without calculating their 10-year ASCVD risk.

In patients aged 40 to 75 years evaluated for primary ASCVD prevention: Have a clinician–patient risk discussion before starting statin therapy.

In nondiabetic patients aged 40 to 75 years and with the following characteristics:

  • LDL-C levels ≥70 mg/dL (≥1.8 mmol/L), at a 10-year ASCVD risk of ≥7.5%: Start a moderate-intensity statin if a discussion of treatment options favors statin therapy.

  • A 10-year risk of 7.5-19.9% (intermediate risk): Risk-enhancing factors favor initiation of statin therapy.

  • LDL-C levels ≥70-189 mg/dL (≥1.8-4.9 mmol/L), at a 10-year ASCVD risk of ≥7.5-19.9%: If a decision about statin therapy is uncertain, consider measuring coronary artery calcium (CAC) levels.

Assess patient adherence and the percentage response to LDL-C–lowering medications and lifestyle changes with a repeat lipid measurement 4-12 weeks after initiation of statin therapy or dose adjustment; repeat every 3-12 months as needed.

2018 USDHHS Physical Activity Guidelines

The guidelines on physical activity were released in November 2018 by the Physical Activity Guidelines Advisory Committee of the USDHHS. [25, 26]

Age- and condition-related recommendations

Children aged 3-5 years: Should be physically active throughout the day to enhance growth and development.

Children aged 6-17 years: Sixty minutes or more of moderate-to-vigorous physical activity per day.

Adults: At least 150-300 minutes per week of moderate-intensity aerobic physical activity, OR 75-150 minutes per week of vigorous-intensity aerobic physical activity, OR an equivalent combination of moderate- and vigorous-intensity aerobic activity; muscle-strengthening activities should be performed on two or more days per week.

Older adults: Multicomponent physical activity to include balance training, aerobic activity, and muscle-strengthening activity.

Pregnant and postpartum women: At least 150 minutes of moderate-intensity aerobic activity weekly.

Adults with chronic conditions or disabilities who are able: Follow key guidelines and perform both aerobic and muscle-strengthening activities.

Sleep, daily functioning, and mental health

Strong evidence demonstrates that moderate-to-vigorous physical activity improves sleep quality by decreasing the time it takes to fall asleep; it can also increase deep-sleep time and decrease daytime sleepiness.

Single episodes of physical activity promote improvements in executive function, to include organization of daily activities and future planning. Cognition (ie, memory, processing speed, attention, academic performance) also can be improved with physical exercise.

Regular physical activity reduces the risk of clinical depression, as well as reducing depressive symptoms and symptoms of anxiety.

Strong evidence demonstrates regular physical activity improves perceived quality of life.

Risk of diseases and conditions

Regular physical activity minimizes excessive weight gain, helps maintain weight within a healthy range, improves bone health, and prevents obesity, even in children as young as 3-5 years.

In pregnant women, physical activity helps reduce excessive weight gain in pregnancy and helps reduce the risk of developing gestational diabetes and postpartum depression.

Regular physical activity has been shown to improve cognitive function and to reduce the risk of dementia; falls and fall-related injuries; and cancers of the breast, esophagus, colon, bladder, lung, endometrium, kidney, and stomach. It also helps retard the progression of osteoarthritis, type 2 diabetes, and hypertension.

Promotion of physical activity

School- and community-based programs can be effective.

Environmental and policy changes should improve access to physical activity and support of physical activity behavior.

Information and technology should be used to promote physical activity, to include activity monitors (eg, wearable devices), smartphone apps, computer-tailored printed material, and Internet-based programs for self-monitoring, message delivery, and support.

For more information, please go to Therapeutic Exercise.

2017 ACC/AHA Classification and Treatment of Hypertension

The ACC/AHA guidelines eliminate the classification of prehypertension and divides it into two levels [27, 28] : (1) elevated blood pressure (BP), with a systolic pressure between 120 and 129 mm Hg and diastolic pressure less than 80 mm Hg, and (2) stage 1 hypertension, with a systolic pressure of 130 to 139 mm Hg or a diastolic pressure of 80 to 89 mm Hg.

In adults at increased risk of heart failure (HF), the optimal BP in those with hypertension should be less than 130/80 mm Hg.

Adults with HFrEF (HF with reduced ejection fraction) and hypertension should be prescribed GDMT (guideline-directed management and therapy) titrated to attain a BP of less than 130/80 mm Hg.

Nondihydropyridine calcium channel blockers (CCBs) are not recommended in the treatment of hypertension in adults with HFrEF.

Adults with hypertension and chronic kidney disease (CKD) should be treated to a BP goal of less than 130/80 mm Hg.

After kidney transplantation, it is reasonable to treat patients with hypertension to a BP goal of less than 130/80 mm Hg.

After kidney transplantation, it is reasonable to treat patients with hypertension with a calcium antagonist on the basis of improved glomerular filtration rate (GFR) and kidney survival.

Immediate lowering of SBP to less than 140 mm Hg in adults with spontaneous intracerebral hemorrhage (ICH) who present within 6 hours of the acute event and have an SBP between 150 mm Hg and 220 mm Hg is not of benefit to reduce death or severe disability and can be potentially harmful.

Adults with acute ischemic stroke and elevated BP who are eligible for treatment with intravenous tissue plasminogen activator should have their BP slowly lowered to less than 185/110 mm Hg before thrombolytic therapy is initiated.

In adults with an acute ischemic stroke, BP should be less than 185/110 mm Hg before administration of intravenous tissue plasminogen activator and should be maintained below 180/105 mm Hg for at least the first 24 hours after initiating drug therapy.

For adults who experience a stroke or transient ischemic attack (TIA), treatment with a thiazide diuretic, ACE inhibitor, or ARB, or combination treatment consisting of a thiazide diuretic plus ACE inhibitor, is useful.

In adults with an untreated SBP greater than 130 mm Hg but less than 160 mm Hg or DBP greater than 80 mm Hg but less than 100 mm Hg, it is reasonable to screen for the presence of white coat hypertension by using either daytime ABPM (ambulatory BP monitoring) or HBPM (home BPM) before diagnosis of hypertension.

In adults with untreated office BPs that are consistently between 120 mm Hg and 129 mm Hg for SBP or between 75 mm Hg and 79 mm Hg for DBP, screening for masked hypertension with home BP monitoring (or ABPM) is reasonable.

In adults with hypertension, screening for primary aldosteronism is recommended in the presence of any of the following concurrent conditions: resistant hypertension, hypokalemia (spontaneous or substantial, if diuretic induced), incidentally discovered adrenal mass, family history of early-onset hypertension, or stroke at a young age (< 40 years).

Adult men and women with elevated BP or hypertension who currently consume alcohol should be advised to drink no more than 2 and 1 standard drinks per day, respectively.

Two or more antihypertensive medications are recommended to achieve a BP target of less than 130/80 mm Hg in most adults with hypertension, especially in black adults with hypertension.

Women with hypertension who become pregnant should not be treated with ACE inhibitors, ARBs, or direct renin inhibitors.

Use of BP-lowering medications is recommended for secondary prevention of recurrent CVD events in patients with clinical CVD and an average SBP of 130 mm Hg or higher or an average DBP of 80 mm Hg or higher, and for primary prevention in adults with an estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk of 10% or higher and an average SBP of 130 mm Hg or higher or an average DBP of 80 mm Hg or higher.

Use of BP-lowering medication is recommended for primary prevention of CVD in adults with no history of CVD and with an estimated 10-year ASCVD risk < 10% and an SBP of 140 mm Hg or higher or a DBP of 90 mm Hg or higher.

Adults with an elevated BP or stage 1 hypertension who have an estimated 10-year ASCVD risk less than 10% should be managed with nonpharmacological therapy and have a repeat BP evaluation within 3 to 6 months.

Adults with stage 1 hypertension who have an estimated 10-year ASCVD risk of 10% or higher should be managed initially with a combination of nonpharmacological and antihypertensive drug therapy and have a repeat BP evaluation in 1 month.

For adults with a very high average BP (eg, SBP ≥180 mm Hg or DBP ≥110 mm Hg), evaluation followed by prompt antihypertensive drug treatment is recommended.

Simultaneous use of an ACE inhibitor, ARB, and/or renin inhibitor is potentially harmful and is not recommended to treat adults with hypertension.

For more information, please go to Hypertension.

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