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Ischemic Heart Disease
Ischemic Heart Disease Lecture Notes
Jill Conway, 9/21/00
Heart disease is responsible for 40% of all U.S. deaths, about 750,000 annually. The major causes of heart disease, in descending order, are 1) IHD, CHD 2) HTN heart disease 3) valvular HD, 4) NIHD, and 5) congenital HD. IHD is responsible for 80-90% of deaths due to cardiac causes.
Normal heart: ~300 gm, RV wall 3-5 mm, LV wall 1.3-1.5 cm
Valves: semilunar valves have three cusps which overlap about 30% in the closed state. Semilunar = aortic and pulmonic. Mitral valve closure marks the beginning of systole.
Atrioventricular valves: mitral and tricuspid. Mitral is a bicuspid valve.
25% of cells in myocardium are myocytes, but these comprise 90% of heart volume since they are large cells. The remainder are ECs associated with capillaries and some connective tissue cells. Purkinje cells with few myofibers help to regulate contraction and disruption of these areas leads to rhythm disturbances. These include the 1) SA node (at right atrium near SVC opening), 2) the AV node (right atrium near IV septum), and 3) the bundle of His that runs down the IV septum into branches that divide into each ventricle.
Blood Supply: coronary circulation occurs mostly during diastole when cardiac relaxation diminishes the pressure in the vasculature. There are three main coronary arteries with specific areas of the heart that they perfuse.
- Left Anterior Descending branch of left coronary artery: supplies anterior LV wall, anterior 2/3 of IV septum, apex of the heart
- Right Coronary artery supplies the RV wall, posterior wall of LV and posterior 1/3 of IV septum
- Left Circumflex artery supplies the lateral LV wall
In 80% of people, there is right dominant circulation, which means that the RCA supplies 1/3 of septum and thus right heart circulatory problems can cause serious LV damage. In 20% of people, the Left Circumflex (LCX) also supplies the posterior 1/3 of the IV septum, called left dominant circulation.
Aging: The aging heart accumulates increased connective tissue and has fewer myocytes with some deposition of amyloid. In addition, myocytes may accumulate lipofuscin and undergo atrophy which leads to the term "brown atrophy" for a smaller and lipofuscin colored heart. Mitral and aortic valves may calcify, leading to stenosis.
Congestive Heart Failure: defined as inability of heart to pump adequately to meet metabolic needs, or the heart becomes effective only at elevated pressures. 300,000 deaths in the US per year, 50% mortality within five years of diagnosis. CHF is the leading diagnosis upon discharge from hospitalization in those over 65. Failure of the heart may arise from inability to eject venous return (backward failure) or "high" output failure where heart cannot eject enough blood to meet elevated systemic demands (forward failure). Another way to classify CHF is as systolic dysfunction that results from LV failure due to ischemia, pressure or volume overload, dilated cardiomyopathy, or as diastolic dysfunction that results from the inability to fill the heart and may occur with excessive LV hypertrophy, fibrosis and constrictive diseases, or amyloid deposits. Many forms of heart disease eventually lead to CHF which can result from left or right sided failure.
Hypertrophy may precede the development of CHF as first the heart tries to compensate either for increased outflow pressure (HTN) or increased fluid load by increasing muscle fiber size and contractile force. Pressure hypertrophy, due to either HTN or aortic stenosis, develops concentrically with a diminished lumen size whereas volume hypertrophy occurs with chamber dilation and may exist with normal wall thickness. Therefore, wall thickness alone cannot indicate the severity of disease.
Decreased CO leads to dilation of chambers from increased volume, stretching of myofibers (eventually past maximal contractile length), and hypertrophy. CHF is considered to be compensated when dilation, hypertrophy, release of catecholamines and increased contractile strength maintains output and decompensated when these mechanisms are no longer adequate. As the compensatory adaptations fail, decreased perfusion coinciding with the stimulus to increase gene expression and upregulate metabolic machinery may accelerate apoptosis of myocytes.
Left ventricular hypertrophy itself is a risk factor for sudden death, independent of CHF, HTN, or atherosclerosis. The enlarged heart has increased metabolic needs in a context of inadequate perfusion. But the pathologic hypertrophy of the ailing heart differs from that of exercise induced cardiac response, which is not associated with increased risks.
Left sided failure: caused by IHD, HTN, valvular disease, dilated LV and reduced compliance. All these increase pulmonary pressure which leads to pulmonary edema, hemosiderin laden macrophages in alveoli ("heart failure cells"), brown induration (hemosiderin and fibrosis), soggy lungs and increased risk of pulmonary infection.
Sx: dyspnea, orthopnea, PND, hemoptysis and eventually cerebral hypoxia, decreased renal perfusion, pre-renal azotemia. Pre-renal azotemia is uremia (BUN (blood urea nitrogen) elevations) that occurs secondary to dysfunction in organs other that diminishes kidney perfusion. In this case, decreased perfusion to the kidneys will activate the renin-angiotensin system which will lead to volume overload in an already failing heart. The heart cannot compensate for the increased load and kidney perfusion will be further diminished, leading to acute tubular necrosis and loss of kidney function causing BUN elevations.
Right sided failure: usually secondary to left sided failure but can be primary from mitral stenosis, congenital left-to-right shunt, cor pulmonale. Causes systemic fluid overload leading to organ damage, including nutmeg liver, splenomegaly, severe prerenal azotemia, peripheral edema, pleural effusions, and DVT with pulmonary embolism.
Patients with clinically significant CHF will often present with signs of both left and right-sided heart failure.
IHD (clinicians usually call this CHD): defined as myocardial oxygen demand that exceeds supply. Single most common cause of death in developed nations, about 500,000 annually in the US. Major cause is coronary AS to with significant lumen reduction. Greater than 90% of IHD patients have severe coronary AS, usually with reduction in lumen size of a major epicardial vessel of greater than 75%.
Clinical presentation does not correlate well with extent of atherosclerosis, however, leading to the hypothesis that acute plaque disruption with plaque hemorrhage, fissuring, ulceration or thrombus formation may cause most of the clinical manifestations of IHD. AMI tends to occur in the a.m. when blood pressure, platelet reactivity, and adrenergic stimulation of the myocardium is high. Smaller and less advanced plaques (50-75% lumen reduction) may be at higher risk of acute events than very severe or advanced ones. In more severe stenosis, there may be more fibrosis, a less dense lipid core, and more lumen occlusion that decreases blood flow and pulsatile stress on the lesion. Other possible causes of acute clinical symptoms include thrombosis and vasospasm. Four distinct IHD clinical syndromes discussed below are angina, MI, CIHD, SCD. Transmural AMI usually arises from a thrombus that leads to complete occlusion of a vessel and subsequent areas of cardiac death. However, angina, subendocardial infarcts, and SCD usually occur when there is less than total occlusion of the vessel by a thrombus.
Angina = reversible chest pain caused by narrowed coronary artery lumen. Stable (or typical angina pectoris) is caused by severe AS and exercise induced, improved by rest and nitroglycerin. Occlusive AS lesions progressively limit the supply of oxygen to the heart. As demand increases with exercise, oxygen delivery cannot keep pace. Stable angina is therefore associated with progressive AS and not with acute events such as thrombosis or plaque rupture.
Prinzmetal's (variant angina) occurs at rest from vasospasm and is unrelated to changes in BP, heart rate or oxygen demand. Responds to nitroglycerin. Unstable (crescendo) angina gets progressively worse and more frequent. May occur at rest and last longer than stable angina. Usually arises an acute change in status such as thrombosis of a fissured AS plaque. Unstable angina signals worsening heart disease and indicates that infarction is likely.
MI = leading cause of US death, occurs at any age but more frequent in men than women, although this differential decreases at increased ages, increased risk in smokers HTN, DM, and hypercholesterolemia. 1.5 million in the US per year, about 500,000 deaths, of which about half occur before arrival at a hospital. Typically presents with chest pain, rapid, weak pulse, sweating, dyspnea, nausea. About 15% are clinically silent.
90% of AMI stems from coronary artery disease with “sudden change” involving fissure and plaque disruption, thrombus formation as platelets aggregate to the subendothelial collagen with eventual occlusion of the arterial lumen. The remaining 10% may result from vasospasm, emboli, or unknown causes. Restoration of blood flow within 20-40 minutes may prevent any significant necrosis. Obstruction of blood flow for longer than 40 minutes normally kills the affected myocardial cells.
Angina precedes MI in 50% of patients. Subendocardial types involve only inner 1/3 to 1/2 of wall. These infarcts may result from severe AS without an acute event such as thrombus formation. Transmural type associated with AS, plaque rupture, platelet aggregation, vasospasm, and occlusive thrombus. Most occur in early a.m. with high platelet counts. Begin in subendocardial myocardium of LV = least well perfused area and once begun, the infarct may spread across the entire wall during the next six hours. If the thrombus is partial and flow is re-established after the occlusion, an AMI will tend to be subendocardial, but if a thrombus is complete, an AMI will tend to be transmural. Most all transmural infarcts involve the LV wall. Most common sites are within proximal 2 cm of LAD. 40-50% or total occur in LAD (affects anterior LV and anterior 2/3 of ventricular septum) 30-40% RCA (posterior LV wall, posterior 1/3 of septum), 15-20% LCX (lateral wall of LV).
Changes seen in light microscopy:
0-30 minutes = none
1-4 hours = cell swelling, fiber waviness (normal cells are stretched when adjacent dead cells fail to contract) may be visible. CKMB rises by 4 hours. CKMB is extremely sensitive but not very specific. Also, it peaks at 24 hours and returns to normal within 72 hours so you can't test for it later. LDH1 rises by 18-36 hours. Troponins (cTn1 and cTnT) are extremely specific and rise in about four hours and stay elevated for 4-7 days.
4-12 hours = coagulation necrosis, edema
12-24 hours = intercellular edema and intense eosinophilia evident on histology, pyknosis of nuclei
24-72 hours = intense inflammatory response with lots of neutrophils visible between myocardial fibers
72 hours - 10 days = organization and lots of granulation tissue
weeks = collagen deposition and loss of vascularity and contraction
2 months = dense collagenous scar without further modification (i.e., you cannot tell a 5 year old infarct from a 2 month old one)
Gross changes: At 0-12 hours, the infarct is not visible. at 12-24 hours, there is pallor and blotchiness in the affected area. At 24-72 hours, the area is soft and pale to yellow. At 3-10 days, the infarct is yellow with a hyperemic border indicating granulation tissue and new vascularity. At several weeks, the infarct is pale gray to whitish, firmer and well demarcated.
Treatment: streptokinase and tissue plasminogen activator can be given early in an MI in order to help thrombolysis. PTCA can both help destroy a thrombus and clear out some of the AS plaque as well.
Complications: Those who survive an initial AMI are at risk for developing further life-threatening complications. 80-90% of patients who survive initially experience complications including arrhythmias (85%) which are especially common with posterior infarcts that may affect the AV node. LV failure may develop if a large portion of the LV wall is compromised and leads to pulmonary edema (60%). Rupture of the ventricular wall usually about 3-7 days after the event occurs when blood ruptures either the exterior LV wall leading to rapid death from cardiac tamponade or rarely through the LV septum, causing a left to right shunt. Rupture occurs in roughly 5% of cases. Mural thrombus may develop over the inflamed and necrotic area in about 30% of patients, leading to concern about emboli traveling to kidney, brain, and GIT. Cardiogenic shock is also a potential complication in 10% of patients and is usually fatal. Left ventricular aneurysm may also develop over the scar in about 10% of long-term survivors.
CIHD: progressive CHF from chronic ischemia. Occurs insidiously in elderly with a long history of angina, often with previous MI. There is gradual loss of cardiac reserve and cardiac atrophy, scarring, and lipofuscin in myocytes. Diagnose by exclusion of other causes only.
Sudden cardiac death: Death within 24 hours of onset of acute sx, usually from IHD and severe AS, usually death occurs within the first hour. First sign of IHD in 50% of patients. Occurs in 25% of acute MI. Obesity and HTN predispose to SCD. Many other causes are not related to AMI such as hypertrophic cardiomyopathy, congenital heart abnormalities, pulmonary hypertension. Mechanism= lethal arrhythmia such as ventricular fibrillation, usually due to irritable myocardium from ongoing ischemia.
Hypertensive Heart Disease: hx of HTN and otherwise unexplained LV hypertrophy caused by HTN which increases O2 demand. LV compliance is reduced, increased myofiber size increases diffusion distance for O2. May occur with sustained BP levels of 140/90. Sx: concentric hypertrophy of LV wall without other causes, headache, dizziness, a-fib, IHD.
Cor Pulmonale: RV enlargement due to primary pulmonary HTN or other primary pulmonary causes. Acute = RV dilation following massive pulmonary embolism but not associated with RV hypertrophy which takes time to develop. Chronic = RV hypertrophy and dilation due to pressure overload, usually secondary to COPD. RV wall enlarges to > 1.0 cm. Associated with chronic bronchitis and emphysema. Causes 10-30% of hospital cardiac admissions.