Ischemic Heart Disease, Pathophysiology, Clinical presentation, Diagnosis & Treatment.

Ischemic Heart Disease

• Ischemic heart disease (IHD) is defined as lack of oxygen and decreased or no blood flow to the myocardium resulting from coronary artery narrowing or obstruction. It may present as acute coronary syndrome (ACS), which includes unstable angina and non–ST-segment elevation (NSTE) or ST-segment elevation (STE) myocardial infarction (MI), chronic stable exertional angina, ischemia without symptoms, or ischemia due to coronary artery vasospasm (variant or Prinzmetal angina). PA

THOPHYSIOLOGY

• Major determinants of myocardial oxygen demand (MVo2) are heart rate (HR), contractility, and intramyocardial wall tension during systole. Because the consequences of IHD usually result from increased demand with a fixed oxygen supply, alterations

in MVo2 are important in producing ischemia and for interventions intended to alleviate it.

• The double product (DP) is the heart rate multiplied by the systolic blood pressure (DP = HR × SBP) and serves as an indirect estimate of MVo2.

• The caliber of resistance vessels delivering blood to the myocardium and MVo2 are the primary determinants in the occurrence of ischemia.

• Large epicardial or surface coronary vessels (R1) offer little resistance to myocardial flow and intramyocardial arteries and arterioles (R2), which branch into a dense capillary network to supply basal blood flow. Under normal circumstances, resistance in R2 is much greater than that in R1. Myocardial blood flow is inversely related to arteriolar resistance and directly related to coronary driving pressure.

• Atherosclerotic lesions occluding R1 increase arteriolar resistance, and R2 can vasodilate to maintain coronary blood flow. With greater degrees of obstruction, this response is inadequate, and the coronary flow reserve afforded by R2 vasodilation is

insufficient to meet oxygen demand. 

• The diameter and length of obstructing lesions and the influence of pressure drop across an area of stenosis also affect coronary blood flow. Dynamic coronary obstruction can occur in normal vessels and vessels with stenosis in which vasomotion or a spasm may be superimposed on a fixed stenosis. Persisting ischemia may promote growth of collateral blood flow.

• Relatively severe stenosis (>70%) may provoke ischemia and symptoms at rest. Lesions creating obstruction of 50% to 70% may reduce blood flow, but these obstructions are not consistent, and vasospasm and thrombosis superimposed on a “noncritical” lesion may lead to clinical events such as MI.

• Regional loss of ventricular contractility may impose a burden on remaining myocardial tissue, resulting in heart failure (HF), increased MVo2, and rapid depletion of blood flow reserve. Zones of tissue with marginal blood flow may develop that are at risk for more severe damage if the ischemic episode persists or becomes more severe. Nonischemic areas of myocardium may compensate for severely ischemic and border zones of ischemia by developing more tension than usual in attempt to maintain cardiac output. The left or right ventricular dysfunction that ensues may be associated with an S3 gallop, dyspnea, orthopnea, tachycardia, fluctuating blood pressure, transient murmurs, and mitral or tricuspid regurgitation. Impaired diastolic and systolic function leads to elevated left ventricular filling pressure.

CLINICAL PRESENTATION

• Many ischemic episodes are asymptomatic (silent ischemia). Patients often have a reproducible pattern of pain or other symptoms that appear after a specific amount of exertion. Increased symptom frequency, severity, or duration, and symptoms at rest suggest an unstable pattern that requires immediate medical evaluation.

• Symptoms may include a sensation of pressure or burning over the sternum or near it, which often radiates to the left jaw, shoulder, and arm. Chest tightness and shortness of breath may also occur. The sensation usually lasts from 30 seconds to 30 minutes.

• Precipitating factors include exercise, cold environment, walking after a meal, emotional upset, fright, anger, and coitus. Relief occurs with rest and within 45 seconds to 5 minutes of taking nitroglycerin.

• Patients with variant (Prinzmetal) angina secondary to coronary spasm are more likely to experience pain at rest and in the early morning hours. Pain is not usually brought on by exertion or emotional stress or relieved by rest; the electrocardiogram (ECG) pattern demonstrates current injury with ST-segment elevation rather than depression.

• Unstable angina is stratified into categories of low, intermediate, or high risk for short-term death or nonfatal MI. Features of high-risk unstable angina include:

(1) accelerating tempo of ischemic symptoms in the preceding 48 hours;

 (2) pain at rest lasting more than 20 minutes; 

(3) age older than 75 years; 

(4) ST-segment changes; and 

(5) clinical findings of pulmonary edema, mitral regurgitation, S3, rales, hypotension, bradycardia, or tachycardia.

• Episodes of ischemia may also be painless, or “silent,” perhaps due to a higher threshold and tolerance for pain than in patients who have pain more frequently.

DIAGNOSIS

• Obtain medical history to identify the nature or quality of chest pain, precipitating factors, duration, pain radiation, and response to nitroglycerin or rest. Ischemic chest pain may resemble pain from noncardiac sources, and diagnosis of anginal pain may

be difficult based on history alone.

• Ask the patient about personal risk factors for coronary heart disease (CHD), including smoking, hypertension, and diabetes mellitus.

• Obtain family history that includes information about premature CHD, hypertension, lipid disorders, and diabetes mellitus.

• Findings on cardiac examination may include abnormal precordial systolic bulge, decreased intensity of S1, paradoxical splitting of S2, presence of S3 or S4, apical systolic murmur, and diastolic murmur.

• Laboratory tests: hemoglobin, fasting glucose (to exclude diabetes), and fasting lipid panel. High-sensitivity C-reactive protein (hsCRP); homocysteine level; evidence of 

Chlamydia infection; and elevations in lipoprotein (a), fibrinogen, and plasminogen activator inhibitor may be helpful. Cardiac enzymes are normal in stable angina. Troponin T or I, myoglobin, and creatinine kinase myocardial band (CK-MB) may

be elevated in unstable angina.

• Resting ECG is normal in about half of patients with angina who are not experiencing acute ischemia. Typical ST–T-wave changes include depression, T-wave inversion, and ST-segment elevation. Variant angina is associated with ST-segment elevation, whereas silent ischemia may produce elevation or depression. Significant ischemia is associated with ST-segment depression greater than 2 mm, exertional hypotension,

and reduced exercise tolerance.

• Exercise tolerance (stress) testing (ETT), thallium myocardial perfusion scintigraphy, radionuclide angiocardiography, ultrarapid computed tomography, and coronary angiography may be performed in certain circumstances. Obtain a chest radiograph if the patient has HF symptoms.

TREATMENT

• Goals of Treatment: Short-term goals are to reduce or prevent anginal symptoms that limit exercise capability and impair quality of life. Long-term goals are to prevent CHD events such as MI, arrhythmias, and HF and to extend the patient’s life.

NONPHARMACOLOGIC THERAPY

• Primary prevention through modification of risk factors should reduce prevalence of IHD. Secondary intervention is effective in reducing subsequent morbidity and mortality.

• Risk factors for IHD are additive and can be classified as alterable or unalterable. Unalterable risk factors include gender, age, family history or genetic composition, environmental influences, and, to some extent, diabetes mellitus. Alterable risk factors include smoking, hypertension, hyperlipidemia, obesity, sedentary lifestyle, hyperuricemia, psychosocial factors such as stress, and use of drugs that may be detrimental (eg, progestins, corticosteroids, calcineurin inhibitors).

PHARMACOLOGIC THERAPY 

β-Adrenergic Blockers

• Decreased HR, contractility, and blood pressure reduce MVo2 and oxygen demand in patients with effort-induced angina. β-Blockers do not improve oxygen supply, and, in certain instances, unopposed α-adrenergic stimulation may lead to coronary vasoconstriction.

• β-Blockers improve symptoms in approximately 80% of patients with chronic exertional stable angina, and objective measures of efficacy demonstrate improved exercise duration and delay in the time at which ST-segment changes and initial or limiting symptoms occur. β-Blockade may allow angina patients previously limited by symptoms to perform more exercise and improve cardiovascular performance through a training effect. 

• Ideal candidates for β-blockers include patients in whom physical activity is a prominent cause of attacks; those with coexisting hypertension, supraventricular arrhythmias, or post-MI angina; and those with anxiety associated with anginal episodes. β-Blockers may be used safely in angina and HF.

• β-Blockade is effective in chronic exertional angina as monotherapy and in combination  with nitrates and/or calcium channel blockers (CCBs). β-Blockers are first line in chronic angina requiring daily maintenance therapy because they are more effective in reducing episodes of silent ischemia and early-morning peak of ischemic activity and improving mortality after Q-wave MI than nitrates or CCBs.

• If β-blockers are ineffective or not tolerated, monotherapy with a CCB or combination therapy may be instituted. Reflex tachycardia from nitrates can be blunted with β-blocker therapy, making this a useful combination.

• Initial doses of β-blockers should be at the lower end of the usual dosing range and titrated to response. Treatment objectives include lowering the resting HR to 50 to 60 beats/min and limiting maximal exercise HR to approximately 100 beats/min or less.

HR with modest exercise should be no more than approximately 20 beats/min above resting HR (or a 10% increment over resting HR).

• There is little evidence to suggest superiority of any particular β-blocker. Those with longer half-lives may be administered less frequently, but even propranolol may be given twice daily in most patients. Membrane-stabilizing activity is irrelevant in angina treatment. Intrinsic sympathomimetic activity appears to be detrimental in patients with rest or severe angina because the reduction in HR would be minimized, limiting reduction in MVo2. Cardioselective β-blockers may minimize adverse effects such as bronchospasm, intermittent claudication, and sexual dysfunction. Combined nonselective β- and α-blockade with labetalol may be useful in patients with marginal left ventricular (LV)

reserve.

• Adverse effects of β-blockade include hypotension, decompensated HF, bradycardia, heart block, bronchospasm, altered glucose metabolism, fatigue, malaise, and depression. Abrupt withdrawal has been associated with increased severity and number of

anginal episodes and MI. Tapering of therapy over several days should minimize risk of withdrawal reactions if therapy is to be discontinued.

Nitrates

• Nitrates reduce MVo2 secondary to venodilation and arterial-arteriolar dilation, leading to a reduction in wall stress from reduced ventricular volume and pressure Direct actions on coronary circulation include dilation of large and small intramural coronary arteries, collateral dilation, coronary artery stenosis dilation, abolition of normal tone in narrowed vessels, and relief of spasm.

• Pharmacokinetic characteristics common to nitrates include large first-pass hepatic metabolism, short half-lives (except for isosorbide mononitrate [ISMN]), large volumes of distribution, high clearance rates, and large interindividual variations in plasma concentrations. The half-life of nitroglycerin is 1 to 5 minutes regardless of the route, hence the potential advantage of sustained-release and transdermal products. Isosorbide dinitrate (ISDN) is metabolized to ISMN. ISMN has a half-life of approximately 5 hours and may be given once or twice daily, depending on the product chosen.

• Nitrate therapy may be used to terminate an acute anginal attack, to prevent effortor stress-induced attacks, or for long-term prophylaxis, usually in combination with β-blockers or CCBs. Sublingual, buccal, or spray nitroglycerin products are preferred for alleviation of anginal attacks because of rapid absorption . Symptoms may be prevented by prophylactic oral or transdermal products (usually in combination with β-blockers or CCBs), but development of tolerance may be problematic.

• Sublingual nitroglycerin, 0.3 to 0.4 mg, relieves pain in approximately 75% of patients within 3 minutes, with another 15% becoming pain free in 5 to 15 minutes. Pain persisting beyond 20 to 30 minutes after use of two or three nitroglycerin tablets suggests ACS, and the patient should be instructed to seek emergency aid. 

• Chewable, oral, and transdermal products are acceptable for long-term prophylaxis. Dosing of long-acting preparations should be adjusted to provide a hemodynamic response. This may require oral ISDN doses of 10 to 60 mg as often as every 3 to 4 hours because of tolerance or first-pass metabolism. Intermittent (10−12 hours on, 12−14 hours off ) transdermal nitroglycerin therapy may produce modest but significant improvement in exercise time in chronic stable angina.

• Adverse effects include postural hypotension with associated central nervous system (CNS) symptoms, reflex tachycardia, headaches and flushing, and occasional nausea. Excessive hypotension may result in MI or stroke. Noncardiovascular adverse effects

include rash (especially with transdermal nitroglycerin), methemoglobinemia with high doses given for extended periods, and measurable ethanol and propylene glycol concentrations with IV nitroglycerin.

• Because both the onset and offset of tolerance to nitrates occur quickly, one strategy to circumvent tolerance is to provide a daily nitrate-free interval of 8 to 12 hours. For example, ISDN should not be used more often than three times daily to avoid tolerance.

• Nitrates may be combined with other drugs with complementary mechanisms of action for chronic prophylaxis. Combination therapy is generally used in patients with more frequent symptoms or symptoms that do not respond to β-blockers alone (nitrates plus β-blockers or CCBs), in patients intolerant of β-blockers or CCBs, and in patients with vasospasm leading to decreased supply (nitrates plus CCBs).

Calcium Channel Blockers

• Direct actions include vasodilation of systemic arterioles and coronary arteries, leading to reduced arterial pressure and coronary vascular resistance, as well as depression of myocardial contractility and conduction velocity of the sinoatrial (SA) and atrioventricular (AV) nodes. Reflex β-adrenergic stimulation overcomes much of the negative inotropic effect, and depression of contractility becomes clinically apparent

only in the presence of LV dysfunction and when other negative inotropic drugs are used concurrently.

• Verapamil and diltiazem cause less peripheral vasodilation than dihydropyridines such as nifedipine but greater decreases in AV node conduction. They must be used with caution in patients with preexisting conduction abnormalities and those taking other drugs with negative chronotropic properties. 

• MVo2 is reduced with all CCBs primarily because of reduced wall tension secondary to reduced arterial pressure. Overall, the benefit provided by CCBs is related to reduced MVo2 rather than improved oxygen supply.

• In contrast to β-blockers, CCBs may improve coronary blood flow through areas of fixed coronary obstruction by inhibiting coronary artery vasomotion and vasospasm.

• Good candidates for CCBs include patients with contraindications or intolerance to β-blockers, coexisting conduction system disease (except for verapamil and diltiazem), Prinzmetal angina, peripheral arterial disease, severe ventricular dysfunction, and concurrent hypertension. Amlodipine is probably the CCB of choice in severe ventricular dysfunction, and the others should be used with caution if the EF is less than 40%.

Ranolazine

• Ranolazine reduces calcium overload in ischemic myocytes through inhibition of the late sodium current. It does not affect HR, inotropic or hemodynamic state, or increase coronary blood flow.

• Ranolazine is indicated for treatment of chronic angina. In controlled trials, it modestly improved exercise time by 15 to approximately 45 seconds compared with  placebo. In a large ACS trial, ranolazine reduced recurrent ischemia but did not

improve the primary efficacy composite end point of cardiovascular death, MI, or recurrent ischemia.

• Because it prolongs the QT interval, reserve ranolazine for patients who have not achieved an adequate response to other antianginal drugs. It should be used in combination with amlodipine, β-blockers, or nitrates.

• Start ranolazine at 500 mg twice daily and increase to 1000 mg twice daily if needed based on symptoms. Obtain baseline and follow-up ECGs to evaluate effects on the QT interval. The most common adverse effects include dizziness, headache, constipation, and nausea.

TREATMENT OF STABLE ISCHEMIC HEART DISEASE

• Guideline-directed medical therapy (GDMT) places a strong emphasis on patient education. Lifestyle modifications include daily physical activity, weight management, dietary therapy, smoking cessation, psychological interventions, limitation of alcohol intake, and management of blood pressure and diabetes.

• β-Blockers may be preferable for chronic prophylaxis because of less frequent dosing and other desirable properties (eg, potential cardioprotective effects, antiarrhythmic effects, lack of tolerance, and antihypertensive efficacy). Patients most likely to respond well to β-blockade are those with a high resting HR and those with a relatively fixed anginal threshold.

• CCBs are as effective as β-blockers and are most useful in patients who have a variable threshold for exertional angina. Calcium antagonists may provide better skeletal muscle oxygenation, resulting in decreased fatigue and better exercise tolerance. They can be used safely in many patients with contraindications to β-blockers. Patients with conduction abnormalities and moderate to severe LV dysfunction (EF <35%) should not be treated with verapamil or diltiazem, whereas amlodipine may be used safely in many of these patients. Diltiazem has significant effects on the AV node and can produce heart block in patients with preexisting conduction disease or when other drugs with effects on conduction (eg, digoxin and β-blockers) are used concurrently. Nifedipine may cause excessive HR elevation, especially if the patient is not receiving a β-blocker, and this may offset its beneficial effect on MVo2. The combination of CCBs and β-blockers is rational because the hemodynamic effect of calcium antagonists is complementary to β-blockade. However, combination therapy may not always be more effective than single-agent therapy.

• Chronic prophylaxis with long-acting forms of nitroglycerin (oral or transdermal), ISDN, ISMN, and pentaerythritol tetranitrate may be effective, but development of tolerance is a limitation. Monotherapy with nitrates should not be first-line therapy

unless β-blockers and CCBs are contraindicated or not tolerated. A nitrate-free interval of 8 hours per day or longer should be provided to maintain efficacy.

• For prophylaxis when undertaking activities that predictably precipitate attacks, nitroglycerin 0.3 to 0.4 mg sublingually may be used approximately 5 minutes prior to the time of the activity. Nitroglycerin spray may be useful when inadequate saliva is produced to rapidly dissolve sublingual nitroglycerin or if a patient has difficulty opening the tablet container. The response usually lasts approximately 30 minutes. 

TREATMENT OF CORONARY ARTERY SPASM AND VARIANT ANGINA PECTORIS

• All patients should be treated for acute attacks and maintained on prophylactic treatment for 6 to 12 months after the initial episode. Aggravating factors such as alcohol or cocaine use and cigarette smoking should be stopped.

• Nitrates are the mainstay of therapy, and most patients respond rapidly to sublingual nitroglycerin or ISDN. IV and intracoronary nitroglycerin may be useful for patients not responding to sublingual preparations.

• Because CCBs may be more effective, have few serious adverse effects, and can be given less frequently than nitrates, some authorities consider them the agents of choice for variant angina. Nifedipine, verapamil, and diltiazem are all equally effective as single agents for initial management. Patients unresponsive to CCBs alone may have nitrates added. Combination therapy with nifedipine plus diltiazem or nifedipine plus verapamil may be useful in patients unresponsive to single-drug regimens.

• β-Blockers have little or no role in the management of variant angina because they may induce coronary vasoconstriction and prolong ischemia.

EVALUATION OF THERAPEUTIC OUTCOMES

• Subjective measures of drug response include number of painful episodes, amount of rapid-acting nitroglycerin consumed, and symptomatic improvement in exercise capacity (ie, longer duration of exercise or fewer symptoms at the same exercise level). Once patients have been optimized on medical therapy, symptoms should improve over 2 to 4 weeks and remain stable until the disease progresses.

• The Seattle Angina Questionnaire, Specific Activity Scale, and Canadian Cardiovascular Society classification system can be used to improve reproducibility of symptom assessment.

• If the patient is doing well, no other assessment may be necessary. Objective improvement may be assessed by increased exercise duration on ETT and absence of ischemic changes on ECG or deleterious hemodynamic changes. Limit use of echocardiography and cardiac imaging to patients not doing well to determine whether revascularization or other measures should be undertaken.

• Monitor for major adverse effects such as headache and dizziness with nitrates; fatigue and lassitude with β-blockers; and peripheral edema, constipation, and dizziness with CCBs.

• A comprehensive plan includes ancillary monitoring of lipid profiles, fasting plasma glucose, thyroid function tests, hemoglobin/hematocrit, and electrolytes