Abu Zubair meriwayatkan dari Jabir bin Abdullah bahwa Nabi Muhammad SAW bersabda:

"Setiap penyakit ada obatnya. Jika obat yang tepat diberikan dengan izin Allah, penyakit itu akan sembuh".

(HR. Muslim, Ahmad dan Hakim).

Kamis, 24 Desember 2009



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.

A complex and incompletely understood interaction exists between the critical cellular elements of the atherosclerotic lesion. These cellular elements are endothelial cells, smooth muscle cells, platelets, and leucocytes. 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 biological processes that contribute to atherogenesis and the clinical manifestations of atherosclerosis.

The mechanisms of atherogenesis remain uncertain. The "response-to-injury" theory is most widely accepted. 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 RNA (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.

The earliest pathologic lesion of atherosclerosis is the fatty streak. The fatty streak is observed in the aorta and coronary arteries of most individuals by age 20 years. The fatty streak 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 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.

These 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. Human coronary arteries enlarge in response to plaque formation, and luminal stenosis may only occur once the plaque occupies greater than 40% of the area bounded by the internal elastic lamina. Developing atherosclerotic plaques acquire their own microvascular network called vasa vasorum, which are prone to hemorrhage and contribute to progression of atherosclerosis.1

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. Furthermore, 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.

United States

In the United States, about 80 million people, or 36.3% of the population, have existing cardiovascular diseases. In addition 795,000 people suffer new or recurrent strokes each year.2

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

The frequency of clinical manifestations of atherosclerosis in Great Britain, west of Scotland in particular, is especially high. The same is true of Finland, in particular, and Scandinavia in general. Russia and many of the former states of the Soviet Union have recently experienced an exponential increase in the frequency of coronary heart disease that likely is the result of widespread economic hardship and social upheaval, a high prevalence of cigarette habituation, and a diet high in saturated fats.

The frequency of coronary heart disease in the Far East is significantly lower than that documented in the West. Ill-defined genetic reasons for this phenomenon may exist, but significant interest surrounds the role of diet and other environmental factors in the absence of clinical atherosclerotic vascular disease in these populations. Atherosclerotic cardiovascular disease is also rare on the African continent, although growing evidence indicates that this too is changing as a result of rapid westernization and urbanization of the traditionally rural and agrarian African populations. The prevalence of coronary heart disease is also increasing in the Middle East, India, and Central and South America.3 The rate of coronary artery disease in ethnic immigrant populations in the United States approaches that of the disease in whites, supporting the role of these putative environmental factors.

Atherosclerosis is the leading cause of death in the developed world, and atherosclerosis is predicted to be the leading cause of death in the developing world within the first quarter of the next century.

In 2005, cardiovascular disease was responsible for 864,5000 deaths, or 35.3% of all deaths that year. They included 151,000 deaths from myocardial infarction and 143,600 deaths from stroke.2
An encouraging decrease in mortality due to coronary heart disease in the developed world has occurred. Unfortunately, this decrease has not occurred in the developing world, and an exponential increase in tobacco habituation and the adoption of a Western diet high in saturated fats likely predicts the continued increase in death and disability due to coronary heart disease.

Atherosclerosis is more common among men than women. The higher prevalence of atherosclerosis in men is thought to be due to the protective effects of the female sex hormones. This sex effect is absent after menopause in women. The incidence of coronary heart disease among women parallels that of men, but women demonstrate an approximately 10-year chronological delay in the onset of clinical manifestations.

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

The symptoms of atherosclerosis are highly variable. Patients with mild atherosclerosis may present with clinically important symptoms and signs of disease and myocardial infarction, or sudden cardiac death may be the first symptom of coronary heart disease. However, many patients with anatomically advanced disease may have no symptoms and experience no functional impairment. Initially thought to be a chronic, slowly progressive, degenerative disease, it is now apparent that atherosclerosis is a disease with 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.

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. This impairment in flow results in symptoms of inadequate blood supply to the target organ in the event of increased metabolic activity and oxygen demand. Stable angina pectoris, intermittent claudication, and mesenteric angina are examples of the clinical consequences of this mismatch.
Rupture of a plaque or denudation of the endothelium overlying a fibrous plaque may result in exposure of the highly thrombogenic subendothelium and lipid core. This exposure may result in thrombus formation, which may partially or completely occlude flow in the involved artery. Unstable angina pectoris, myocardial infarction, transient ischemic attack, and stroke are examples of the clinical sequelae of partial or complete acute occlusion of an artery. Atheroembolism is a distinct clinical entity that may occur spontaneously or as a complication of aortic surgery, angiography, or thrombolytic therapy in patients with advanced and diffuse atherosclerosis.
Angina pectoris is characterized by retrosternal chest discomfort that typically radiates to the left arm and may be associated with dyspnea. Angina pectoris is exacerbated by exertion and relieved by rest or nitrate therapy. Unstable angina pectoris describes a pattern of increasing frequency or intensity of episodes of angina pectoris and includes pain at rest. A prolonged episode of angina pectoris that may be associated with diaphoresis is suggestive of myocardial infarction.
Stroke, reversible ischemic neurological deficit, and transient ischemic attack are a range of manifestations of impairment of vascular supply to the central nervous system and are characterized by the sudden onset of a focal neurological deficit of variable duration, respectively.
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.
Visceral ischemia may be occult or symptomatic prior to symptoms and signs 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.
Atheroembolism may present with symptoms of digital necrosis, gastrointestinal bleeding, myocardial infarction, retinal ischemia, cerebral infarction, and renal failure.


The physical signs of atherosclerosis provide objective evidence of extracellular lipid deposition, stenosis or dilatation of large muscular arteries, or target organ ischemia or infarction.

Hyperlipidemia - Xanthelasma, tendon xanthomata
Coronary artery disease - Fourth heart sound, tachycardia, hypotension, hypertension
Cerebrovascular disease - Diminished carotid pulses, carotid artery bruits, focal neurological deficits
Peripheral vascular disease - Decreased peripheral pulses, peripheral arterial bruits, pallor, peripheral cyanosis, gangrene, ulceration
Abdominal aortic aneurysm - Pulsatile abdominal mass, peripheral embolism, circulatory collapse
Atheroembolism - Livedo reticularis, gangrene, cyanosis, ulceration (The presence of pedal pulses in the setting of peripheral ischemia suggests microvascular disease and includes cholesterol embolization.)
Valvular heart disease (particularly calcific aortic stenosis, now recognized to be linked to atherosclerosis) – Cardiac murmur

A number of large epidemiological 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 risk factors and include hyperlipidemia, hypertension, cigarette habituation, diabetes mellitus, age, and sex. More recently, 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.

Hyperlipidemia: Hyperlipidemia and dyslipidemia are established risk factors for atherosclerosis. Convincing evidence exists that lowering serum cholesterol reduces the risk of subsequent coronary heart disease events and overall mortality. For additional resources, visit Hyperlipidemia.
Hypertension is a risk factor for the development of atherosclerosis, atherosclerotic cardiovascular disease, and stroke. 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 hyperlipidemia, hypertension, diabetes mellitus, obesity, and physical inactivity. For additional resources, visit Hypertensive Heart Disease.
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. Hypertension has been shown, in both epidemiologic and experimental studies, to accelerate atherosclerotic vascular disease and increase the incidence of clinical complications.
Diabetes mellitus: An important risk factor for hyperlipidemia and atherosclerosis and 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 are two to four times more likely to develop coronary heart disease than non-smokers and they have double the risk for stroke.2 The mechanisms are complex and likely multifactorial and result in endothelial dysfunction and a relatively hypercoagulable state. It is known that after smokers give up smoking, their risk of mortality and future cardiac events declines, although whether cardiovascular risk for former smokers ever reaches that of never smokers. Using data from the Third National Health and Nutrition Examination Survey (NHANES III), researchers found that the smoking-associated inflammatory response subsides within 5 years after smoking cessation, suggesting that the cardiovascular risk subsides gradually with reduced exposure.4
Metabolic syndrome
In recent years, air pollution has gained increasing recognition as a contributing modifiable risk factor in the urban communities.5 The mechanism is thought to be through the participation of combustion-derived nanoparticles acting through proinflammatory or alternatively direct cardiac toxic pathways.

Of note, algorithms for predicting the risk of cardiovascular disease have generally been developed for a follow-up period of 10 years or less. Clustering of risk factors at younger ages and increasing life expectancy suggest the need for longer-term risk prediction.

In a 2009 study, Pencina and colleagues constructed an algorithm for predicting 30-year risk of coronary death, myocardial infarction, or stroke—"hard" CVD events. Prospective 30-year follow-up of 4,506 participants of the Framingham Offspring cohort showed that standard risk factors (male sex, systolic blood pressure, antihypertensive treatment, total and high-density lipoprotein cholesterol, smoking, and diabetes mellitus), measured at baseline, were significantly related to the incidence of hard cardiovascular disease and remained significant when updated regularly on follow-up. Body mass index was associated positively with 30-year risk of hard CVD only in models that did not update risk factors.6
Novel risk factors: The established risk factors noted above successfully predict future cardiac events in about 50-60% of patients. In recent years, a concerted effort to identify and validate new markers of future risk of the clinical consequences of atherosclerosis has been made.
C-reactive protein: Baseline C-reactive protein (CRP) levels add to the predictive value of lipid parameters in determining the risk of first myocardial infarction in apparently healthy men and women without a history of coronary heart disease. Baseline CRP levels also were found to be predictive of symptomatic peripheral vascular disease in a cohort of healthy men. 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 this is a truly modifiable risk factor remains unclear. Some early evidence exists that risk factor modification, particularly the use of aspirin and the hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, may reduce plaque inflammation.7
Fibrinogen: Fibrinogen may be elevated in association with risk factors for atherosclerosis, including smoking, age, and diet; however, recent evidence suggests that elevated levels of fibrinogen are a strong independent predictor of future cardiovascular events in apparently healthy patients and patients with a prior history of cardiovascular disease. This association may be as strong as the established association between hypercholesterolemia and coronary heart disease.
Lipoprotein (a): Numerous studies have linked elevated plasma levels of lipoprotein (a), an LDL-like moiety that circulates in the blood attached to apolipoprotein (a), with the development of coronary artery disease. This complex shares structural domains with the fibrinolytic enzyme plasminogen and may render the molecule prothrombotic. The LDL-like moiety is susceptible to oxidation and may be particularly atherogenic. However, the results of prospective studies have been discordant and have not proven the relationship between elevated plasma levels of lipoprotein (a) and coronary artery disease inconclusively. Niacin is known to reduce plasma levels of lipoprotein (a), although whether this truly is a modifiable risk factor remains unclear.


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