ks:8,20,3,15,27,III 1a.

Etiologi Chest Pain Heart-related causes Examples of heart-related causes of chest pain include:

Heart attack. A heart attack is a result of a blood clot that's blocking blood flow to your heart muscle. Angina. Thick plaques can gradually build up on the inner walls of the arteries that carry blood to your heart. These plaques narrow the arteries and restrict the heart's blood supply, particularly during exertion.

Aortic dissection. This life-threatening condition involves the main artery leading from your heart your aorta. If the inner layers of this blood vessel separate, blood will be forced between the layers and can cause the aorta to rupture.

Pericarditis. This condition, an inflammation of the sac surrounding your heart, is short-lived and often related to a viral infection.

Digestive causes Chest pain can be caused by disorders of the digestive system, including:

Heartburn. This painful, burning sensation behind your breastbone occurs when stomach acid washes up from your stomach into the esophagus the tube that connects your throat to your stomach.

Swallowing disorders. Disorders of the esophagus can make swallowing difficult and even painful. Gallbladder or pancreas problems. Gallstones or inflammation of your gallbladder or pancreas can cause abdominal pain that radiates to your chest.

Muscle and bone causes Some types of chest pain are associated with injuries and other problems affecting the structures that make up the chest wall. Examples include:

Costochondritis. In this condition, the cartilage of your rib cage, particularly the cartilage that joins your ribs to your breastbone, becomes inflamed and painful. Sore muscles. Chronic pain syndromes, such as fibromyalgia, can produce persistent muscle-related chest pain. Injured ribs. A bruised or broken rib can cause chest pain.

Lung-related causes Many lung disorders can cause chest pain, including:

Pulmonary embolism. This cause of chest pain occurs when a blood clot becomes lodged in a lung (pulmonary) artery, blocking blood flow to lung tissue. Pleurisy. If the membrane that covers your lungs becomes inflamed, it can cause chest pain that's made worse when you inhale or cough. Collapsed lung. The chest pain associated with a collapsed lung typically begins suddenly and can last for hours. A collapsed lung occurs when air leaks into the space between the lung and the ribs.

Pulmonary hypertension. High blood pressure in the arteries carrying blood to the lungs (pulmonary hypertension) also can produce chest pain.

Other causes Chest pain can also be caused by:

Panic attack. If you experience periods of intense fear accompanied by chest pain, rapid heartbeat, rapid breathing, profuse sweating and shortness of breath, you may be experiencing a panic attack.

Shingles. Caused by a reactivation of the chickenpox virus, shingles can produce pain and a band of blisters from your back around to your chest wall.

1b. Mekanisme chest pain Keadaan iskemik akan mengeksitas reseptor kemosensitif dan mekanoreseptif di jantung. Stimulasi dari reseptor2 ini akan mengakibatkan pelepasan adenosine, bradikinin, dan substansi lainnya yang mengeksitasi ujung sensoris saraf afferen simpatis dan

vagal.Syaraf afferen melintasi nervi yang menghubungkan 5 thoracic ganglia atas dan 5 distal thoracic root di medula spinalis Impuls ditransmisikan oleh medula spinalis ke thalamus, lalu ke neocortex. Vanilloid Receptor-1 (VR1) ada pada ujung saraf sensoris pada jantung dan berperan dalam transduser iskemia jaringan. Nyeri merupakan sebuah mekanisme kardioprotektif untuk mengurangi beban kerja jantung pada keadaan iskemia. (sumber: Braunwalds text book) The mechanisms of cardiac pain and the neural pathways involved are poorly understood. It is presumed that angina pectoris results from ischemic episodes that excite chemosensitive and mechanoreceptive receptors in the heart. Stimulation of these receptors results in the release of adenosine, bradykinin, and other substances that excite the sensory ends of the sympathetic and vagal afferent fibers. The afferent fibers traverse the nerves that connect to the upper five thoracic sympathetic ganglia and upper five distal thoracic roots of the spinal cord. Impulses are transmitted by the spinal cord to the thalamus and hence to the neocortex. Data from animal studies have identified the vanilloid receptor-1 (VR1), an important sensor for somatic nociception, to be present on the sensory nerve endings of the heart and have suggested that VR1 functions as a transducer of myocardial tissue ischemia.[6]

1d. Hubungan gender dan usia pada kasus Gender dan usia tertentu merupakan factor resiko terjadinya Acute Coronary Syndrome. Semakin bertambahnya usia, efectivitas otot jantung dlaam memompa berkurang, adanya arterosklerosis. 1f. Makna klinis chest pain sejak 3 jam yang lalu: Interpretasi EKG:

Cardiac Enzyme: 1g. Mekanisme nyeri alih pada kasus Pada medula spinalis, impuls simpatis afferen dari jantung bisa bertemu dengan impuls somatis dari thorax, sehingga menimbulkan nyeri alih. Pada kasus ini, syaraf kardiak vagal afferen pada nucleus tractus solitarius medulla lalu menjalar turun untuk meneksitasi spinothalamic tract cell pada cervical atas sehingga menimbulkan neri pada leher dan rahang (sumber: Braunwalds textbook)

1h Jenis jenis chest pain / bisa juga DD

4a. Indikasi treadmill test

4b.Tujuan treadmill test Untuk mendiagnosis IHD dan menentukan prognosis dengan mencari tanda yang tipikal pada EKG yang ditempel pada pasien dengan stress fisik. 4c. Cara treadmill test Tes ini terdiri dari peningkatan beban kerja eksternal secara bertahap dengan memonitor simtomp, EKG, dan tekanan darah lengan. Tes dihentikan apabila pasien mengalami chest discomfoort, sesak napas, pusing, kelelahan berat, depresi ST segment >0,2 mV (2mm), penurunan tekanan sistolik hingga > 10 mmHg, dan adanya ventricular tachyarrhythmia.

4d. Interpretasi treadmill test

The ischemic ST-segment response is generally defined as flat or downsloping depression of the ST segment >0.1 mV below baseline (i.e., the PR segment) and lasting longer than 0.08 s (Fig. 237-1). Upsloping or junctional ST-segment changes are not considered characteristic of ischemia and do not constitute a positive test. Although Twave abnormalities, conduction disturbances, and ventricular arrhythmias that develop during exercise should be noted, they are also not diagnostic. Negative exercise tests in which the target heart rate (85% of maximal predicted heart rate for age and sex) is not achieved are considered to be nondiagnostic.

When interpreting ECG stress tests, the probability that coronary artery disease (CAD) exists in the patient or population under study (i.e., pretest probability) should be considered. Overall, false-positive or false-negative results occur in one-third of cases. However, a positive result on exercise indicates that the likelihood of CAD is 98% in males >50 years with a history of typical angina pectoris and who develop chest discomfort during the test. The likelihood decreases if the patient has atypical or no chest pain by history and/or during the test. The incidence of false-positive tests is significantly increased in patients with low probabilities of IHD, such as asymptomatic men under the age of 40 or in premenopausal women with no risk factors for premature atherosclerosis. It is also increased in patients taking cardioactive drugs, such as digitalis and antiarrhythmic agents, or in those with intraventricular conduction disturbances, resting ST-segment and T-wave abnormalities, ventricular hypertrophy, or abnormal serum potassium levels. Obstructive disease limited to the circumflex coronary artery may result in a false-negative stress test since the lateral portion of the heart which this vessel supplies is not well represented on the surface 12lead ECG. Since the overall sensitivity of exercise stress electrocardiography is only ~75%, a negative result does not exclude CAD, although it makes the likelihood of threevessel or left main CAD extremely unlikely. The physician should be present throughout the exercise test, and it is important to measure total duration of exercise, the times to the onset of ischemic ST-segment change and chest discomfort, the external work performed (generally expressed as the stage of exercise), and the internal cardiac work performed, i.e., by the heart rateblood pressure product. The depth of the ST-segment depression and the time needed for recovery of these ECG changes are also important. Because the risks of exercise testing are small but realestimated at one fatality and two nonfatal complications per 10,000 tests equipment for resuscitation should be available. Modified (heart ratelimited rather than symptom-limited) exercise tests can be performed safely in patients as early as 6 days after uncomplicated MI (Table 237-2). Contraindications to exercise stress testing include rest angina within 48 h, unstable rhythm, severe aortic stenosis, acute myocarditis,

uncontrolled heart failure, severe pulmonary hypertension, and active infective endocarditis. The normal response to graded exercise includes progressive increases in heart rate and blood pressure. Failure of the blood pressure to increase or an actual decrease with signs of ischemia during the test is an important adverse prognostic sign, since it may reflect ischemia-induced global LV dysfunction. The development of angina and/or severe (>0.2 mV) ST-segment depression at a low workload, i.e., before completion of stage II of the Bruce protocol, and/or ST-segment depression that persists for >5 min after the termination of exercise increases the specificity of the test and suggests severe IHD and a high risk of future adverse events.

5. Merokok Merokok menurunkan kadar HDL, merusak endotel, meningkatkan koagubilitas darah, meningkatkan sekresi katekolamin yang dapat menyebabkan vasokonstriksi, memicu arterosklerosis. may increase myocardial O2 demand and reduce coronary blood flow by means of an alpha-adrenergically mediated increase in coronary artery tone and thereby cause acute ischemia.

7a. Interpretasi hasil lab: Hb WBC ESR Platelet Total Cholestrol Trigliseride LDL HDL Blood glucose Urine Glucose CK NAC CK MB Troponin T Diff Count Hasil 14 g/dL 9800/mm3 20 mm 214000/mm3 345 mg% 180 mg% 194 mg% 38 mg% 155 mg/dL 373 U/L 67 U/L 0,2 ng/mL 0/2/5/65/22/6 Nilai Normal 13-18 g/dL (laki) 4500 - 11000 mm3 0-15 mm 150000 400000 mm3 < 200 mg% 40 150 mg% 60 180 mg% 30 80 mg% 70 100 mg/dL 96 140 U/L (P) 38 174 U/L (L) < 25 U/L <0,03 ng/ml Basofil : 0 1 (%) Eosinofil : 1 3 (%) Batang : 2 6 (%) Segmen : 50 70 (%) Limfosit : 20 40 (%) Monosit : 2 8 % . 7b. Mekanisme abnormalitas pada hasil lab Types of cardiac markers include the following: Sensitivity and specificity The most sensitive and specific test for myocardial damage. Troponin test Because it has increased specificity compared with CKMB, troponin is a superior marker for 12 hours Approximate peak Interpretasi Normal Normal Tinggi Normal Tinggi Tinggi Tinggi Normal Tinggi Normal Tinggi Tinggi Tinggi Normal

Test

Description Troponin is released during MI from the cytosolic pool of the myocytes. Its subsequent release is prolonged with degradation of actin and myosin filaments. Differential diagnosis of troponin elevation includes acute infarction, severe pulmonary embolism causing acute

right heart overload, heart failure, myocarditis. Troponins can also calculate infarct size but the peak myocardial injury. must be measured in the 3rd day. After myocyte injury, troponin is released in 24 hours and persists for up to 7 days. CK-MB resides in the cytosol and facilitates movement of high energy phosphates into and out of It is relatively Creatine Kinase (CK-MB) test specific when skeletal muscle damage is not present. 1024 hours mitochondria. It is distributed in a large number of tissues even in the skeletal muscle. Since it has a short duration, it cannot be used for late diagnosis of acute MI but can be used to suggest infarct extension if levels rise again. This is usually back to normal within 23 days. Lactate dehydrogenase catalyses the conversion of pyruvate to lactate. LDH-1 isozyme is normally found in the heart muscle and Lactate dehydrogenase (LDH) LDH-2 is found predominately in LDH is not as specific as troponin. 72 hours blood serum. A high LDH-1 level to LDH-2 suggest MI. LDH levels are also high in tissue breakdown or hemolysis. It can mean cancer, meningitis, encephalitis, or HIV. this usually back to normal 1014 Aspartate transaminase days. This was the first used.[4] It is not specific for heart damage, and it is

(AST)

also one of the liver function tests. Myoglobin is used less than the other markers. Myoglobin is the primary oxygen-carrying pigment of muscle tissue. It is high when muscle tissue is damaged but it 2 hours lacks specificity. It has the advantage of responding very rapidly,[5] rising and falling earlier than CK-MB or troponin. It also has been used in assessing reperfusion after thrombolysis.[6] IMA can be detected via the albumin cobalt binding (ACB) test, a limited available FDA approved assay. Myocardial ischemia alters the N-terminus of albumin reducing the ability of cobalt to bind to albumin. IMA measures ischemia

Myoglobin (Mb)

low specificity for myocardial infarction

Ischemiamodified albumin (IMA) low specificity

in the blood vessels and thus returns results in minutes rather than traditional markers of necrosis that take hours. ACB test has low specificity therefore generating high number of false positives and must be used in conjunction with typical acute approaches such as ECG and physical exam. Additional studies are required. This is increased in patients with heart failure. It has been approved as a marker for acute congestive

Pro-brain natriuretic peptide

heart failure. Pt with < 80 have a much higher rate of symptom free survival within a year. Generally, pt with CHF will have > 100. Glycogen phosphorylase isoenzyme BB (abbreviation: GPBB) is an isoenzyme of glycogen phosphorylase. Glycogen phosphorylase exists in 3 isoforms. One of these Isoforms is GP-BB. This isoform exists in heart and brain tissue. Because of the blood brain barrier GP-BB can be seen as heart muscle specific. During the Glycogen phosphorylase isoenzyme BB high sensitivity and specificity early after 7 hours chest pain process of ischemia, GP-BB is converted into a soluble form and is released into the blood. This isoform of the enzyme exists in cardiac (heart) and brain tissue. GP-BB is one of the "new cardiac markers" which are discussed to improve early diagnosis in acute coronary syndrome. A rapid rise in blood levels can be seen in myocardial infarction and unstable angina. GP-BB elevated 13 hours after process of ischemia. Mekanisme abnormalitas pada hasil lab: About Troponin

Troponin is a component of the heart's muscle fibers, and the level of troponin in the blood is considered the most important cardiac marker used for assessing heart attacks. Troponin is the most sensitive (that is, it can be detected at low levels) and specific (its presence has a high probability of indicating cardiac muscle damage) of the cardiac markers. When the heart is deprived of oxygen, the muscle fibers are damaged, and their components (including troponin) leak in to the bloodstream. Within 3 to 4 hours after a heart attack, blood levels of two types of troponin (cTnI and cTnT) begin to increase. Troponin levels peak at about 12 to 16 hours and stay elevated for up to 2 weeks. Blood is usually drawn to check troponin levels as an individual arrives at the hospital with chest pain, and then they are checked every 4 to 6 hours after that. Higher troponin levels indicate greater heart muscle damage, but even smaller heart attacks can be detected by measuring troponin. About Creatine Kinase (CK) These enzymes are important participants in the chemical reactions that are necessary for the heart muscle's quick generation of energy. CK, however, is not just present in heart muscle cells; it's actually present inside all muscle cells throughout the body, as well as in brain and lung cells. Since different forms of CK may be increased because of skeletal muscle injury, liver disease or kidney disease, a specialized test is used to determine what percentage of the total CK is due to the type produced by damaged heart muscles (called "CK-MB"). After a heart attack, levels of CK-MB follow a particular, predictable pattern. CK-MB levels begin to rise within about 3 to 6 hours after a heart attack, with the highest CK-MB levels occurring about 12 to 24 hours after the heart attack. Within about 12 to 48 hours of a heart attack, the CK-MB in the bloodstream will return to normal levels. To see this pattern, a series of blood tests will be drawn at various times after the start of the patient's initial symptoms -- usually immediately upon arrival at the hospital, and then every 6 to 8 hours for the next 24 hours.

About Myoglobin (Mb) Myoglobin is a protein found in both skeletal and heart muscle. Although myoglobin levels are not specific for heart damage, they rise very early in a heart attack, making them useful for the early, provisional detection of a heart attack. Myoglobin rises within about 2 hours of a heart attack, peaks at 8 to 12 hours after the heart attack and returns back to normal levels at about 20 to 36 hours after the heart attack. Myoglobin levels are usually drawn upon arrival at a hospital, and then every 2 to 3 hours thereafter for several cycles. A persistently normal myoglobin level can rule out heart muscle damage. Although an elevated myoglobin can suggest a heart attack, because myoglobin can be elevated in many other conditions, an elevated troponin level is required to make a definitive diagnosis. sedimentation rate is a reflection of inflammation in the body. Inflammation in the heart is part of myocardial infarction. The inflammatory cells local to the inflammation signal back to the liver to increase inflammatory proteins. These proteins result in the increased sedimentation rate.

9. Diagnosis Banding pada kasus ini

10. Penatalaksanaan Tata Laksana Pra Rumah Sakit

a. Bagi orang awam mengenali gejala serangan jantung dan segera mengantar pasien mencari pertolongan ke Rumah sakit atau menelpon RS terdekat meminta dikirimkan ambulan beserta petugas kesehatan terlatih. b. Petugas kesehatan atau dokter umum di klinik: - mengenali gejala SKA dan pemeriksaan EKG bila ada - Tirah baring dan pemberian oksigen 2-4 L/menit - Berikan aspirin 160- 325 mg tablet kunyah bila tidak ada riwayat alergi aspirin. - Berikan preparat nitrat sublingual misalnya isosorbid dinitrat 5 mg dapat diulang setiap 5-15 menit sampai 3 kali. - Bila memungkinkan pasang infus. - Segera kirim ke RS terdekat dengan fasilitas ICCU yang memadai dengan pemasangan selang oksigen dan didampingi dokter/paramedik yang terlatih. Tata Laksana Di Unit Gawat Darurat - Tirah baring - Pemberian oksigen 2-4 L/menit untuk mempertahankan saturasi oksigen > 95%. - Pasang infus dan pasang monitor. - Pemberian aspirin 150-325 mg tablet kunyah bila belum diberikan sebelumnya dan tidak ada riwayat alergi aspirin.

- Pemberian nitrat: bisa diberikan nitrat oral sublingual yaitu isosorbid dinitrat 5 mg dapat diulang setiap 5 menit sampai 3 kali untuk mengatasi nyeri dada. - Klopidogrel dosis awal 300 mg, kemudian dilanjutkan 75 mg/ hari - Segera pindahkan ke ICCU. Tata Laksana Di ICCU - Pasang monitor 24 jam - Tirah baring - pemberian oksigen 3-5 L/menit - Pemberian nitrat, bila nyeri belum berkurang dapat diberikan nitrogliserin drip intravena secara titrasi sesuai respon tekanan darah, dimulai 5-10 mikrogram/menit dan dosis dapat ditingkatkan 5-20 mikrogram/menit sampai nyeri berkurang atau Mean Arterial Pressure (MAP) menurun 10% pada normotensi dan 30% pada hipertensi, tetapi tekanan darah sistolik harus > 90 mmHg. - Penyekat Beta bila tidak ada kontraindikasi terutama pada pasien SKA dengan hipertensi dan takiaritmia yaitu bisoprolol mulai 2,5-5mg atau metoprolol 25-50mg atau atenolo 25-50mg. - ACE inhibitor, diberikan pada pasien infark anterior, kongesti paru atau fungsi ventrikel kiri yang rendah dengan EF <>100mmHg. - Pemberian ARB bila pasien intoleran dengan ACE inhibitor. - Atasi nyeri dengan morfin sulfat IV 2-4 mg dengan interval 5-15 menit bila nyeri belum teratasi.

- Pemberian Laksantif untuk memperlancar defekasi. - Anti ansietas: diazepam 2x5mg atau alprazolam 2x0,25mg - Heparinisasi pada kondisi: infark anterior luas, fungsi ventrikel buruk, resiko tinggi trmbosis, fibrilasi atrial, trombus intra kardiak dan onset nyeri dada >12 jam tanpa tindakan revaskularisasi. - Terapi perfusi: fibrinolitik dan intervensi koroner perkutan (PCI).

Atasi komplikasi : Fibrilasi atrium, Fibrilasi ventrikel, Takikardia ventrikel, Bradiaritmia & blok, Perikarditis. Gagal jantung akut, edema paru, syok kardiogenik diterapi sesuai standar pelayanan medis. Komplikasi mekanik : ruptur m. Papillaris, ruptur septum ventrikel, ruptur dinding ventrikel ditatalaksana dengan operasi. 11. Komplikasi Angina pektoris tidak stabil : payah jantung, syok kardiogenik, aritmia, infark miokard akut Infark miokard akut (dengan atau tanpa ST elevasi) : gagal jantung, syok kardiogenik, ruptur korda, ruptur septum, ruptur dinding bebas, aritmia gangguan hantaran, aritmia gangguan pembentukkan rangsang, perikarditis, sindrom Dresler, emboli paru.

+ Pencegahan Sekunder ( farmako ) Additional Pharmacotherapy for Secondary Prevention

ASPIRIN (see Chaps. 45 and 82) .

A meta-analysis of 140,000 patients in 300 studies has confirmed the prophylactic benefit of aspirin in men and women with angina pectoris, previous MI, or stroke and after bypass surgery. In a Swedish trial of men and women with chronic stable angina, 75 mg of aspirin in conjunction with the beta blocker sotalol conferred a 34 percent reduction in acute myocardial infarction and sudden death. In a smaller study confined to men with chronic stable angina but without a history of myocardial infarction, 325 mg of aspirin on alternate days reduced the risk of myocardial infarction by 87% during 5 years of followup. Therefore, administration of aspirin daily is advisable in patients with chronic stable angina but without contraindications to this drug. [13] [50] Dosing at 75 to 162 mg daily appears to have comparable effects for secondary prevention with dosing at 160 to 325 mg daily[65] and appears to be associated with lower bleeding risk. Therefore, aspirin 75 to 162 mg daily is preferred for secondary prevention in the absence of recent intracoronary stenting.[47] Although warfarin has proved beneficial in patients after MI, no evidence supports the use of chronic anticoagulation in patients with stable angina.
CLOPIDOGREL.

Another orally acting class of agents that blocks platelet aggregation is the thienopyridine derivatives, including clopidogrel. Clopidogrel may be substituted for aspirin in patients with aspirin hypersensitivity or those who cannot tolerate aspirin (see Chap. 82) .[47] In a randomized comparison between clopidogrel and aspirin in patients with established atherosclerotic vascular disease (the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events [CAPRIE] trial), treatment with clopidogrel resulted in a modest 8.7 percent relative reduction in the risk of vascular death, ischemic stroke, or myocardial infarction (P = 0.043) over 2 years. Studies evaluating the addition of clopidogrel to aspirin in patients with non-ST elevation acute coronary syndromes or after percutaneous coronary intervention[66] have indicated robust risk reductions. However, the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization Management and Avoidance (CHARISMA) trial has shown no overall benefit of the addition of clopidogrel to aspirin with respect to the primary endpoint of cardiovascular death, MI, or stroke over a median of 28 months (6.8 versus 7.3 percent; P = 0.22) in patients with clinically evident cardiovascular disease (N = 12,153) or multiple risk factors (N = 3284).[67] Subgroup

analyses from the trial have demonstrated a 1 percent lower risk of these events (6.9 versus 7.9 percent; P = 0.046) with the addition of clopidogrel to aspirin for those with established vascular disease, supporting a hypothesis of a potential modest benefit from clopidogrel in patients with established CAD taking aspirin.[67]
BETA BLOCKERS.

The value of beta blockers in reducing death and recurrent myocardial infarction in patients who have experienced a myocardial infarction is well established (see Chap. 51) , as is their usefulness in the treatment of angina. Moreover, patients receiving beta blockers for hypertension are more likely to present with stable angina rather than MI as their first manifestation of CAD.[68] Whether these drugs are also of value in preventing infarction and sudden death in patients with chronic stable angina without previous infarction is uncertain and, despite at least one observational study suggesting lower mortality in the patients who were taking beta blockers,[69] there have been no controlled trials against placebo. However, there is no reason to assume that the favorable effects of beta blockers on ischemia and perhaps on arrhythmias should not apply to patients with chronic stable angina pectoris. Therefore, it is sensible to use these drugs when angina, hypertension, or both are present in patients with chronic CAD and when these drugs are well tolerated.
ACE INHIBITORS.

Although ACE inhibitors are not indicated for the treatment of angina, these drugs appear to have important benefits in reducing the risk of future ischemic events in some patients with cerebrovascular disease (CVD). An unexpected finding from randomized trials of ACE inhibitors in postinfarction and other patients with ischemic and nonischemic causes of LV dysfunction was the striking reduction in incidence of subsequent ischemic events such as myocardial infarction, unstable angina, and the need for coronary revascularization procedures. The potentially beneficial effects of ACE inhibitors include reductions in LV hypertrophy, vascular hypertrophy, progression of atherosclerosis, plaque rupture, and thrombosis, in addition to a potentially favorable influence on myocardial O2 supply and demand relationships, cardiac hemodynamics, and sympathetic

activity. ACE inhibitors enhance coronary endothelial vasomotor function in patients with CAD. In addition, in vitro experiments have shown that angiotensin II induces inflammatory changes in human vascular smooth muscle cells, and treatment with ACE inhibitors can reduce signs of inflammation in animal models of atherosclerosis.[62] Two trials have provided strong evidence supporting the therapeutic benefit of ACE inhibitors in patients with normal LV function and absence of heart failure ( Fig. 54-6 ). In the Heart Outcomes Protection Evaluation (HOPE) study, ramipril significantly decreased the risk of the primary composite endpoint of cardiovascular death, myocardial infarction, and stroke from 17.7 to 14.1 percent (relative risk reduction of 22 percent; P<0.001) compared with placebo in 9297 patients with atherosclerotic vascular disease or diabetes mellitus. In addition, the European Trial on Reduction of Cardiac Events with Perindopril in stable CAD (EUROPA) provided additional convincing support for the benefit of ACE inhibitors, with a 20 percent relative reduction in the risk of cardiovascular death, MI or cardiac arrest in 13,655 patients with stable CAD in the absence of heart failure.[70] In contrast, trandolapril, administered to a target dose of 4 mg daily, showed no effect on the risk of cardiovascular death, MI, or coronary revascularization (21.9 versus 22.5 percent; P = 0.43) in 8290 patients with stable CAD and preserved LV function receiving intensive preventive therapy, usually including revascularization and lipid-lowering agents (see Fig. 54-6 ).[40] Notably, in patients with evidence of renal dysfunction (estimated glomerular filtration rate lower than 60 ml/min/1.73 m2), trandolapril was associated with lower all-cause mortality.[71] Hence, ACE inhibitors are recommended for all patients with CAD with left ventricular dysfunction and for those with hypertension, diabetes, or chronic kidney disease.[47] ACE inhibitors may be considered for optional use in all other patients with normal LV ejection fraction and cardiovascular risk factors that are well controlled in whom revascularization has been performed.[47]
ANTIOXIDANTS (see Chap. 45) .

Oxidized LDL particles are strongly linked to the pathophysiology of atherogenesis, and descriptive, prospective cohort, and case-control studies have suggested that a high

dietary intake of antioxidant vitamins (A, C, and beta-carotene) and flavonoids (polyphenolic antioxidants), naturally present in vegetables, fruits, tea, and wine, is associated with a decrease in CAD events. Clinical data have also suggested that supplementation of vitamin E and C slows atherosclerosis progression assessed by carotid intima-media thickness.[72] However, the Heart Protection Study Collaborative Group enrolled more than 20,000 individuals with established atherosclerotic vascular disease or diabetes mellitus and found no reduction in all-cause mortality, myocardial infarction, or other vascular events with supplementation of vitamin E, vitamin C, and beta-carotene versus matched placebo during 5 years of follow-up.[73] Moreover, supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in two large randomized trials of therapy to lower homocysteine in patients with vascular disease. [79] [80] Thus, based on current evidence, there is no basis for recommending that individuals take supplemental folate, vitamin E, vitamin C, or beta-carotene for the purpose of treating CAD. [13] [50]