Cardiology Core Curriculum A problem-based approach - part 2 pot

Cardiac stress tests are designed to quantitate the cardiovascular responses to controlled incremental increases in metabolic demands using conventional protocols. Stress tests fall into two categories: physical exercise and pharmacologic. Irrespective of the type of stress test protocol used, the measurements routinely obtained include heart rate and blood pressure, electrocardiograms at each incremental increase in workload, and a continuous account of symptoms. Stress testing is frequently performed in combination with imaging techniques, or various nuclear cardiac imaging techniques, which allow additional measurements to be made during stress testing, including ventricular contractile performance (i.e. ejection fraction, regional left ventricular wall motion, and myocardial perfusion and metabolism). Exercise stress tests Exercise stress tests are conducted either on a treadmill or a bicycle ergometer. Exercise is begun at a low workload that the patient can easily sustain. The workload is then increased in increments at regular intervals predefined by the exercise protocol until the patient: • achieves the maximum exercise workload of the protocol • achieves 85% of their predicted heart rate for age and sex • achieves his or her anaerobic threshold • develops typical symptoms with electrocardiographic evidence of ischemia • becomes hypotensive, or • develops ventricular dysrhythmias. All of these are reasons to terminate any and every stress test, whether exercise or pharmacologic. Pharmacologic stress tests Pharmacologic stress tests are used in patients who cannot engage in physical exercise for various reasons. They are conducted by administering a drug that either increases myocardial workload (dobutamine) or vasodilates the coronary microvasculature (dipyridamole or adenosine). Abnormal findings Abnormal findings during stress that reflect impaired performance of the coronary circulation and the myocardium are as follows. Cardiology Core Curriculum 52 • Characteristic electrocardiographic changes occur during exercise when the increased myocardial metabolic activity provokes myocardial ischemia, that is ≥2 mm of planar depression of the ST segments in the electrocardiographic leads that represent the distribution of the stenotic coronary artery (Figure 2.12). • Myocardial ischemia is frequently accompanied by a decline in left ventricular contractile performance heralded by hypotension, which denotes proximal severe triple coronary artery stenoses, stenosis of the left main coronary artery, or ventricular dysfunction. Decline in left ventricular contractile function can be detected by imaging studies conducted during or immediately following stress. • The increased cardiac workload associated with stress may provoke abnormalities and non-uniformities of myocardial coronary perfusion, which may be detected by imaging studies conducted immediately following stress. Alternatively, they may result in electrical irritability and ventricular arrhythmias that are evident electrocardiographically. Cardiac non-invasive imaging and stress testing 53 Baseline ECG Stress ECG IVR VL VF VR VL VF V 3 V 6 V 1 V 2 V 4 V 5 V 3 V 6 V 2 V 5 V 1 V 4 I II II III III Figure 2.12 A pre-exercise (upper) and post-exercise (lower) 12-lead electrocardiogram (ECG) demonstrating normal ST segments at rest, which become significantly depressed (below baseline) diffusely in both anterolateral (leads V 2 –V 6 ) and inferior (leads II, III, and aVF) distribution. The diffuse changes and ST elevation in lead aVR suggest severe left mainstem or proximal left anterior descending coronary artery stenosis as the anatomic lesion responsible for the electrocardiographic abnormalities Cardiac nuclear imaging Cardiac nuclear imaging provides important information on cardiac function by employing radiotracer techniques and external detection equipment. The most frequently used nuclear techniques are myocardial perfusion imaging, radionuclide angiography, and metabolic imaging. Cardiac nuclear imaging is based on the detection of γ rays emitted by radiopharmaceutical agents administered to patients and measured by large detectors (i.e. γ cameras) outside the body. The images created represent various functions of the heart depending on the type of radiopharmaceutical employed. We briefly discuss radiopharmaceuticals and detection systems below. Radiopharmaceuticals Radiopharmaceuticals are compounds that have two distinct elements. One is the radioactive material, called a radionuclide, which is attached to a molecule that distributes in the body according to a given physiologic function. Radionuclides are unstable elements that decay to a more stable state by emitting particles or photons from their nuclei that can be detected. This process is called radioactive decay. In general, radioactive decay may occur in one of three forms: α, β, and γ. Both α and β decay involve the emission of particles, whereas γ decay is characterized by the emission of γ rays (electromagnetic radiation). Clinical nuclear imaging is based entirely on γ emitting radionuclides because γ rays pose the least harmful effect to tissues while having sufficient penetrating power to traverse the body tissues and be detected externally. The most widely used radionuclide for clinical testing is technetium-99m (Tc-99m). This radionuclide is produced by a generator made of molybdenum-99, which decays to Tc-99m and emits γ rays of 140 KeV (kiloelectron volts) energy. Tc-99m decays with a half-life of 6 hours. Another type of radionuclide used in cardiac imaging is the positron emitting radioisotope. This element decays by emitting a “positron” from the nuclei, which is a particle of the same energy (511 KeV) as an electron but is positively charged. This particle immediately interacts with an electron in the surrounding matter in a process known as annihilation. Two γ rays of the same energy and opposite direction are emitted from that process. An example of a positron emitting radionuclide is fluorine-18, which has a half-life of 110 min. The radionuclides above can be attached to other molecules that have a known distribution in the body and thus form a Cardiology Core Curriculum 54 radiopharmaceutical agent. An example of a radiopharmaceutical is Tc-99m sestamibi, which is a myocardial blood flow (MBF) tracer made of two components: the radionuclide (i.e. Tc-99m) and the pharmaceutical (i.e. sestamibi). Sestamibi distributes in the myocardium in proportion to MBF, and its distribution pattern can be detected because of the presence of technetium in the molecule. In patients who have suffered heart attacks, abnormal distribution of tracer helps to define the area of infarction. 12 Detection systems The overall principle of the detection system is based on the theory that certain types of crystal emit light when struck by γ rays. One example of this type of crystal is sodium iodide, which is used in most clinical scanners. The light output of the crystal is amplified many times by photomultiplier tubes and by complex electronic circuitry. This light output can be localized to represent a three-dimensional map of radionuclide distribution within the myocardium. With the aid of computers, this information is digitized and images produced and displayed on computer screens or x ray film. Large detectors, called γ cameras, are used to image large parts of the body. The cameras may produce a single image in a given projection (planar technique) with respect to the organ of interest (for example, heart or liver), or multiple projections that can be reconstructed into images known as tomograms. The advantage of the tomographic method is that the three-dimensional distribution of the radiopharmaceutical may be determined in detail while avoiding the overlap of structures that occurs with planar images. This technique is called single photon emission computed tomography (SPECT) and is designed to image radionuclides that emit single photons. The other major technique available is known as positron emission tomography (PET), which is an imaging method used to detect positron emitting radionuclides. This is a more complex, but more accurate method and is based on a principle called coincidence counting. Positron emitting isotopes decay by giving off two γ rays in exactly opposite directions, each with the same energy. Using sophisticated electronics, the origin of the γ rays may be localized within the body more precisely, resulting in a three-dimensional map of perfusion or metabolism, depending on the tracer used (see below). Myocardial perfusion imaging Myocardial perfusion tracers are used to estimate non-invasively the relative amounts of blood flow to various regions of the heart. Cardiac non-invasive imaging and stress testing 55 This test is the most commonly used technique in cardiac nuclear imaging. In this section we briefly discuss the various radiotracers available for the assessment of regional myocardial perfusion. We review a number of tracers based on the mechanism by which these radiopharmaceuticals measure MBF. Broadly speaking, there are two major categories of myocardial perfusion tracers (Table 2.1): those that are retained in the myocardium and those that are diffusible. Mechanically retained, or labeled albumin microspheres are not used clinically because they are large particles (15 µm in diameter), which if injected intravenously become trapped in the lung capillaries rather than in the myocardium. In order to be used as myocardial perfusion tracers, these microspheres must be injected into the left sided circulation via a catheter placed into the left atrium or ventricle, which involves a more invasive procedure. Tracers retained in the myocardium via non-mechanical means are the most commonly used perfusion agents in clinical practice. These tracers are retained in the myocardium in proportion to MBF, and include thallium-201 and Tc-99m sestamibi for SPECT imaging, and nitrogen-13-ammonia and rubidium-82 for PET imaging. The retention process takes place during the first few minutes after tracer injection, and the distribution of activity represents the blood flow at the time of the injection. This characteristic allows us to image Cardiology Core Curriculum 56 Table 2.1 Summary of tracers used in myocardial perfusion imaging Type of tracer Examples Retained in myocardium Mechanical retention Technetium-99, * carbon-11 † (based on microsphere or gallium-68 † labeled size) albumin microspheres Metabolic retention Thallium, * rubidium-82, † potassium analogs (Na/K energy requiring pump), nitrogen-13 ammonia † (retained as glutamine) Retained in proportion Technetium-99 sestamibi to electrical membrane gradients Diffusible Hydrophilic Oxygen-15 water † Lipophilic Carbon-11 or oxygen-14 butanol † Partially diffusible Technetium-99 teboroxime * These tracers may be used in * single photon emission computed tomography (SPECT) and † positron emission tomography (PET). patients beginning several minutes after the injection, and permits longer scan times, which improves image resolution. Further improvements in resolution are possible using a new acquisition method synchronized to the cardiac cycle, which also provides information on left ventricular wall thickening – a measure of regional function. The ability of tracers to remain in the myocardium for minutes to hours after administration allows us to perform interventions such as exercise or pharmacologic stress testing in patients and then image MBF during flexible time intervals afterward. The most typical example is the perfusion study performed with exercise. Exercise is performed in the exercise laboratory, adjacent to the imaging room, with patients using a treadmill or bicycle ergometer. The perfusion tracer is administered at peak exercise, and the patient is allowed to recover for a few minutes to an hour (depending on the radioisotope), followed by perfusion imaging. Typically, with thallium agents, a resting scan is performed approximately 3 hours after the stress imaging, to allow for comparison with the stress state (Figure 2.13). A smaller dose of thallium is usually given just before the rest image in order to detect better ischemic but viable myocardium. Patients with severely ischemic myocardium may be imaged at 24 hours to allow for further redistribution of the isotope. Using a tracer with a longer half-life and higher energy such as technetium sestamibi has an important practical advantage in that higher quality images are obtained. Thus, the stress intervention can be performed before the resting examination and, should the stress perfusion images be normal, this will eliminate the need for a resting examination. None of the diffusible tracers are used clinically because of the complicated scanning techniques required. However, these techniques are very accurate for quantifying MBF and are used mainly for clinical research. An example of this group of agents is oxygen-15 water, which is employed with PET scanning. Imaging protocols Myocardial perfusion imaging is usually performed with some form of stress test when used for the diagnosis of coronary artery disease (CAD) or for evaluation of treatment in patients with known CAD (for example, angioplasty, bypass surgery, or medications). Stress testing is necessary to detect regional differences in myocardial perfusion due to occlusive CAD, because MBF at rest is not decreased even in the presence of coronary stenoses with up to 80% reduction in normal vessel diameter. By increasing MBF with exercise or coronary vasodilators such as dipyridamole or adenosine, myocardial regions supplied by significantly diseased coronary vessels may be detected because of their inability to increase MBF to a degree similar to that in regions supplied by normal vessels. Cardiac non-invasive imaging and stress testing 57 Given that the radiopharmaceuticals are carried in the blood and extracted by the myocardium, significantly less tracer is distributed to areas supplied by diseased vessels, and therefore the total amount of radiotracer delivered to these regions is less than to normal areas. This result produces a low intensity segment, or defect, on the scan in regions subserved by diseased vessels, and permits not only the detection of the presence of CAD but also assists with localizing the disease to specific coronary arteries (Figure 2.14). The most frequently used stress test in clinical practice is the exercise test. With exercise, there is an increment in heart rate, blood pressure, and contractility that increases with myocardial metabolism, and in turn increases MBF in order to increase oxygen delivery to meet the increased myocardial oxygen demand. An appropriate increment in MBF in response to the oxygen demand can be reached in those segments of the myocardium that are supplied by non-stenotic arteries. This increment in MBF with maximal exercise or maximal vasodilatation is called the coronary flow reserve, and is approximately three to four times the normal resting MBF. Cardiology Core Curriculum 58 Figure 2.13 A normal thallium perfusion scan is shown that illustrates the three views used for planar clinical cardiac imaging. In the short axis view the right ventricle is faintly seen to the left of the image, adjacent to the interventricular septum. The left ventricular (LV) lateral wall is seen to the right of the image. In the horizontal long axis image, the LV apex is at the top of the image, and the lateral wall is to the right. In the vertical long axis view, the anteroseptum is seen at the top of the image, and the LV apex is to the right. Note the homogeneous intensity pattern in all LV myocardial regions However, in segments perfused by a stenotic artery there is an additional resistance in the vessel that prevents an appropriate increment in MBF. Therefore, patients with CAD will not match their increased myocardial oxygen demand, resulting in an imbalance between oxygen demand and supply and producing myocardial ischemia. This supply/demand mismatch and ischemia may result in a typical syndrome of retrosternal chest pain associated with sweating, shortness of breath, and radiation of the pain along the left arm to the elbow or fingers (angina). In other patients, there may be few or no symptoms at all, despite electrocardiographic changes demonstrating myocardial ischemia (silent ischemia). Under these conditions normally perfused myocardium will demonstrate high MBF and the region supplied by the stenotic vessel will have lower MBF. If we inject a myocardial perfusion tracer at this point, the resulting image will Cardiac non-invasive imaging and stress testing 59 Figure 2.14 Perfusion defects. A transient per fusion defect is seen in the upper panel that is consistent with exercise-induced ischemia. During stress, the inferior walls in both the short axis and vertical long axis views exhibit decreased signal intensity, and therefore decreased perfusion, relative to the remaining walls. The signal intensity normalizes or reverses in the resting image, demonstrating a reversible defect. In the lower panel, a fixed defect in a similar location is shown. A defect noted on the stress images show no reversibility upon rest, which is consistent with infarction or non-viable tissue. Reinjection of a small amount of thallium at the time of rest images improves detection of severely ischemic but viable myocardium show a regional perfusion imbalance or defect that is not present in a resting image, when MBF would be more comparable. There are pharmacologic stress tests that can be used to provoke these same transient perfusion defects, which involve the use of potent coronary vasodilators or β-agonists that increase myocardial oxygen consumption in a similar manner to exercise. Clinical applications The major clinical applications of myocardial perfusion imaging are: • diagnosis of CAD • risk stratification in patients with known chronic CAD • treatment evaluation in patients with known CAD, in particular following revascularization techniques such as percutaneous transluminal coronary angioplasty or coronary artery bypass grafting • risk stratification after acute myocardial infarction • evaluation of patients with CAD and left ventricular dysfunction • evaluation of patients with “silent ischemia”. Radionuclide angiography Ventricular function is most commonly assessed with a technique called multigated image acquisition scanning, which uses a “blood pool” method approach. Blood labeled with technetium-99 remains in the intravascular space, or blood pool, and provides a means to measure the end-diastolic and end-systolic volumes (EDV and ESV, respectively) of the heart non-invasively. The ejection fraction, or (EDV – ESV)/EDV, is a common measure of global ventricular performance. If a stress test is performed after baseline imaging, then the cardiac “reserve” can be estimated, with a fall in exercise ejection fraction indicating abnormal reserve. Metabolic imaging PET scanning is a technique that can assess myocardial perfusion and metabolism somewhat more rigorously than thallium scanning. 13 Nitrogen-13-ammonia is a common perfusion isotope, while 18 fluorine deoxyglucose is used as the metabolic tracer that evaluates the ability of myocytes to use glucose (Figure 2.15). One potential advantage to PET scanning is that the study may be performed at rest; however, the use of the above isotopes requires a cyclotron for production. Cardiology Core Curriculum 60 Cardiac non-invasive imaging and stress testing 61 Figure 2.15 In this positron emission tomography (PET) image, the perfusion agent nitrogen-13 ammonia ( 13 NH 3 ; upper panels) demonstrates decreased resting blood flow to the lateral wall, as seen in both the short axis and horizontal long axis views. The metabolic tracer 2-deoxy-2-[ 18 F]fluoro-D-glucose ( 18 FDG) depicts regions in which the conversion from free fatty acid substrate use (normal metabolism) to glycolytic metabolism (ischemic zones) has occurred. High signal intensities in the 18 FDG images (bottom panels) are seen in segments corresponding to the hypoperfused regions, which is indicative of ischemia-related changes in metabolism Case studies Case 2.1 A 32-year-old male tax accountant presented with a 2 year history of progressive shortness of breath on exertion such that he could only walk two blocks on flat ground or climb five stairs. He had never complained of chest pain or palpitations, and was a non-smoker and non-drinker. When aged 15 years, at a school sports medical examination, a cardiac murmur was detected. In his remote past he had sustained two unexplained syncopal episodes that were unrelated to exertion or posture. His father, who had always enjoyed good health as an active athlete and non-smoker, died suddenly from a “heart attack” at age 37 years. His father’s death prompted an office visit to a cardiologist who, in addition to eliciting an ejection systolic murmur at the left sternal edge, recorded a 12-lead electrocardiogram, which revealed left ventricular hypertrophy and repolarization abnormalities. A clinical working diagnosis of congenital aortic valve stenosis was [...]... blocking agents may be efficacious in the treatment of non-sustained ventricular tachycardia Answer to question 6 Non-sustained ventricular tachycardia correlates with sudden death, which accounts for the yearly attrition rate of approximately 5–8% of patients with familial hypertrophic cardiomyopathy Case 2. 2 A 47-year-old female Asian immigrant was brought to the emergency room with a dominant sided... declined cardiac catheterization but agreed to have an echocardiogram and was discharged home on digoxin 0 25 mg/day, furosemide 40 mg/day, potassium supplements, and warfarin at a dose to maintain an International Normalized Ratio of 2 5–3·0 Examination Physical examination: the patient had a right-sided neurologic deficit She was only comfortable at 45° Pulse: 1 52 beats/min, irregularly irregular Blood pressure:... coronary disease (his father had had two myocardial infarctions at ages 50 and 57 years, one brother had coronary artery bypass graft surgery at age 53 years, and his eldest brother had a myocardial infarction at age 56 years but is now symptom free on medical therapy) Examination Physical examination: the patient appeared normal Pulse: 78 beats/min, normal character Blood pressure: 135/80 mmHg Jugular venous... fields 24 -Hour ambulatory electrocardiographic monitoring: predominant cardiac rhythm was sinus, occasional isolated premature ventricular depolarizations, and three episodes of non-sustained ventricular tachycardia, with the longest being an 11-beat run at a maximum rate of 178 beats/min 62 Cardiac non-invasive imaging and stress testing Transthoracic two-dimensional echocardiogram Asymmetric hypertrophy... coronary artery disease Equivocal non-invasive evaluation Persistent chest pain despite negative non-invasive tests Dilated cardiomyopathy Sudden cardiac death Intolerant of medications Patients refractory to Limiting angina despite medical therapy for adequate drug therapy ischemia Unstable angina Postmyocardial infarction angina Positive predischarge exercise test following myocardial infarction Markedly... coronary artery disease included a family history (his father had sustained a myocardial infarction at age 61 years and underwent coronary artery bypass vein grafting; his mother and younger brother had hypertension), he was not diabetic or a smoker, and had a cholesterol of 23 0 mg % (5·9 mmol/l) Examination Physical examination: the patient was in acute distress, and was cold, clammy, and complaining... mmHg Jugular venous pulse: 12 cm at 45° Cardiac impulse: parasternal lift, palpable P2 First heart sound: loud Second heart sound: split with loud P2 At apex was opening snap close to P2 Mid-diastolic murmur at apex Chest examination: normal air entry, basal crepitations Abdominal examination: enlarged, tender liver No peripheral edema Carotid pulses: normal, no bruits Investigations Laboratory findings:... chronic rheumatic heart disease The right axis deviation and right ventricular hypertrophy are due to pulmonary hypertension, and the T and ST abnormalities are digitalis effects Answer to question 6 Left atrial enlargement, prominence of the left atrial appendage and main pulmonary artery, elevated left main bronchus, intracardiac calcification of the mitral valve apparatus, and cephalization of the... and normal, the right atrium and right ventricle were both dilated with moderate tricuspid regurgitation through a normal tricuspid valve A small hemodynamically unimportant pericardial effusion was present Doppler assessment revealed a peak gradient across the mitral valve of 28 mmHg (mean 14 mmHg) and a valve orifice area of 0·7 cm2 calculated from the pressure half-time, and a pulmonary artery systolic... cardiac output (ml/min) and HR is the heart rate For the aortic valve, FP is the systolic filling period (in seconds) and k 86 Cardiac catheterization equals 44·3 For the mitral valve, FP is the diastolic filling period and k equals 37·7 Valve replacement is appropriate in patients who are symptomatic and have a valve area of 1·0 cm2 or less Angiography Angiography is an integral part of the catheterization . electrolytes, and creatinine. Aspartate aminotransferase 198 U/l (3·3 µkat/l); alanine aminotransferase 33 U/l (5·6 µkat/l); International Normalized Ratio 1·3. Electrocardiogram: atrial fibrillation at. furosemide 40 mg/day, potassium supplements, and warfarin at a dose to maintain an International Normalized Ratio of 2 5–3·0. Examination. Physical examination: the patient had a right-sided neurologic. tachycardia correlates with sudden death, which accounts for the yearly attrition rate of approximately 5–8% of patients with familial hypertrophic cardiomyopathy. Case 2. 2 A 47-year-old female