Clinical Aerospace Cardiovascular Medicine

James R. Strader Jr.

Gary W. Gray

William B. Kruyer

I was gratified to be able to answer promptly. I said, “I don’t know”.

—Mark Twain

Cardiovascular diseases (CVDs) will always be a major concern for aeromedical disposition and aircrew standards because they are a major health problem worldwide and a leading cause of mortality and morbidity in industrialized nations. Cardiac diagnoses are frequent causes of loss or restriction of licensure for all categories of civilian and military flying. Most requests for special issuance to fly with a cardiac disorder are for cases of coronary artery disease (CAD), including coronary revascularization (e.g., bypass surgery, stent). Cardiac dysrhythmias and valvular disorders are also common causes for medical review of flying eligibility.

Rapid advancements in cardiology present both challenges and benefits to aeromedical applications. This chapter can neither cover all cardiac diagnoses nor cover any in great detail. Topics of key aeromedical relevance will be discussed, including disposition of various electrocardiographic findings, CAD and CAD intervention, valvular disorders, and tachyarrhythmias. These discussions should also serve as an example of an aeromedical approach to other cardiac diagnoses.

A seven-step process for aeromedical decision making of cardiac diagnoses has been previously proposed and is briefly summarized and discussed as follows (1):

Establish a threshold of acceptable risk for aeromedically pertinent cardiac events. Annual event rates greater than threshold would be unacceptable for continued flying.
Select appropriate aeromedical events for the cardiac diagnosis under consideration.
Determine annual event rates for these selected events.
Address any special considerations, such as high +G_z or single-pilot operations.
If continued flying is a consideration, a recertification policy must be formulated.
Other aeromedical endpoints not considered in the second step should be assessed.
And finally, consider the impact of medical therapy for the diagnosis being addressed.

In this process, aeromedical decisions are based on percent per year event rates at 1 to 3 years to address short-term safety and possibly at 5 to 10 years to address the longer-term likelihood of a continued aviation career. Data from aircrew populations and carefully selected populations from the clinical literature would be used. Within the selected threshold (e.g., 1% per year), sudden and complete incapacitation (sudden cardiac death, syncope) is of key importance but all events that may negatively affect proper performance of flying duties should be considered.

The earlier process and the following discussions of select cardiac disorders address applications to aviation, especially military and commercial aviation. This process applies readily to other special environments such as space flight while taking into consideration potentially different risk thresholds due to length of the space mission, isolation, and so on.

Aeromedical decision making may involve aircrew with symptomatic, clinical heart disease. For this, helpful clinical literature is usually available. However, aeromedical decision making must often consider aircrew with asymptomatic, subclinical disease for which helpful literature may be lacking or incomplete. And at times, a disease is not under consideration, but rather an abnormal test suggesting presence of disease [e.g., electrocardiogram (ECG) or graded exercise test]. The aeromedical issue then becomes estimating the risk of underlying heart disease and deciding to what extent this risk should prudently be pursued with further testing. These challenges are the bedrock of aerospace cardiology.

DISPOSITION OF ELECTROCARDIOGRAPHIC FINDINGS

A resting 12-lead ECG is required for routine surveillance of many aircrew positions but is somewhat of an enigma. Some ECG findings [e.g., left axis deviation (LAD), ST-T wave changes, and ventricular ectopy] are correlated with advancing age and an increased incidence of CAD and hypertension, and may have some predictive value. Yet, these same findings are often nonspecific, not reflective of underlying pathology, and often not evaluated in a clinical scenario. The aeromedical dilemma is to balance the pursuit of underlying disease against the unnecessary performance of tests, which themselves may prompt further testing.

When a minor ECG abnormality presents, comparison to prior tracings is often very helpful to determine aeromedical disposition. An ECG finding that has been present and stable for several years may not require evaluation, whereas an abrupt, new finding compared to prior ECG tracings may warrant thorough investigation. The diagnostic criteria for each of these findings are not discussed; rather the reader is referred to standard ECG textbooks.

Many ECG findings occur with such frequency and benignity that they may be considered normal variants, which do not require further evaluation. A list of suggested normal variants is in Table 13-1. This is not intended to be an all-inclusive list. Moreover certainly for individual cases, the aeromedical practitioner may choose to further evaluate any of these findings.

Conduction Disturbances

Right Bundle Branch Block

Incomplete right bundle branch block (RBBB) is a common ECG finding and is considered a normal variant (Table 13-1). Complete RBBB, reported in 0.2% to 0.4% of military aviators, has not been associated with increased risk of progressive conduction system disease or other cardiac problems in aviator populations (1,2). Echocardiography may be aeromedically prudent to exclude structural heart disease. If normal, unrestricted civilian and military flying duties may be allowed, including entry into military flying training. Periodic reassessment does not appear to be indicated.

TABLE 13-1

Normal Variant Electrocardiographic Findings
Sinus Bradycardia	Right Axis Deviation
Sinus tachycardia	Indeterminate axis
Sinus arrhythmia	Early repolarization ST segment elevation
Sinus pause of 3 s or less	Nonspecific interventricular conduction delay with QRS width <0.12 s
Ectopic atrial rhythm	Terminal conduction delay (wide S wave)
Wandering atrial pacemaker	Incomplete right bundle branch block
Junctional rhythm	RSR’ pattern in leads V1 and/or V2
Idioventricular rhythm	R wave taller than S wave in V1
First-degree atrioventricular (AV) block	Supraventricular or ventricular escape beats
Mobitz I (Wenckebach) AV block	Rare supraventricular or ventricular ectopy

Left Bundle Branch Block

Reported in 0.01% to 0.1% of military aviators, the prevalence of left bundle branch block (LBBB) increases with age as does the prevalence of CAD and hypertension. Rare in aviators aged 35 years or younger, LBBB became more common with advancing age older than 35 years (1,2). Aeromedical concerns are the association of LBBB with CAD and dilated cardiomyopathy. In the absence of underlying heart disease, LBBB does not present a significant risk for cardiac events, especially in the relatively young, healthy aviator population. Evaluation of underlying disease is required, but accuracy of exercise testing and nuclear myocardial perfusion imaging is limited by the LBBB itself. ECG ST-segment response during graded exercise testing is not interpretable in the presence of LBBB, and myocardial perfusion imaging is often abnormal in the anteroseptal region. Conventional coronary angiography remains the gold standard for definitely excluding underlying CAD, but is associated with inherent risks. Depending on the aircrew position, computed tomographic (CT) angiography might be considered to exclude most significant coronary lesions. However, approximately 25% of lesions may be incorrectly assessed by this method. Detection of coronary calcification should be as useful for screening as in other populations, although data are not available regarding its efficacy in LBBB. Detection of coronary calcification is discussed later in this chapter.

Experience with United States Air Force (USAF) aviators has revealed underlying CAD in approximately 10%, twice the estimated background incidence. Licensing authorities must consider whether initial assessment of LBBB should include invasive or noninvasive coronary angiography. For many years, the USAF has returned aviators with LBBB to unrestricted flying, if coronary angiography and noninvasive testing are normal. Periodic noninvasive reassessment is appropriate, especially if coronary angiography is not performed during initial evaluation. LBBB can be an early manifestation of dilated cardiomyopathy reinforcing the importance of regular follow-up.

Nonspecific Intraventricular Conduction Delay

Nonspecific intraventricular conduction delay (IVCD) is considered a normal variant in otherwise healthy subjects if the QRS interval is less than 120 ms. If the QRS interval is 120 ms or greater, the IVCD is considered abnormal but the risk of underlying disease and prognosis are unclear. Reported prevalence in military aviators is similar to RBBB. If underlying cardiac disease is present, cardiomegaly is often a feature. Evaluation with echocardiography and, at least in older aviators, graded exercise testing with nuclear or
echocardiographic stress imaging, should suffice to exclude underlying disease. In the absence of underlying cardiac disease, return to unrestricted flying duties appears indicated. Periodic reassessment may be appropriate.

Left Anterior and Posterior Hemiblock and Bifascicular Block

Prevalence of left anterior hemiblock (LAHB) and left posterior hemiblock (LPHB) has been reported to be 0.9% and 0.1%, respectively, in military aviators (1,2). ECG textbooks often indicate a significant likelihood of underlying cardiac disease, especially for LPHB. This has not been the case in the military aviator population; underlying cardiac disease is uncommon. Prognosis appears to be normal if no underlying cardiac disease is detected by noninvasive evaluation. Return to unrestricted flying duties may then be recommended without future reassessment.

These ECG findings do warrant investigation, especially if new compared to prior ECGs. Extent of evaluation may depend on the age of the individual and overall CAD risk profile. For the young, low-risk aviator (age 35 or younger), echocardiography may be sufficient. For the older or higher-risk aviator, echocardiography and graded exercise testing are recommended. In the absence of abnormal test results, periodic reassessment does not appear to be necessary.

The prevalence of bifascicular block (combination of RBBB and LAHB or LPHB) is not described for aircrew or other healthy populations. Studies of aviators with RBBB, however, have not shown any increased incidence of underlying disease for bifascicular block compared to RBBB with normal axis. Evaluation and disposition of bifascicular block should therefore be comparable to those of RBBB or of hemiblock alone.

Right and Left Axis Deviation

Axis deviations are not conduction disturbances but are discussed here because there is probably considerable overlap between them and the corresponding hemiblocks. Disposition of axis deviation is a common question for the aeromedical practitioner. Concern is whether axis deviation is a marker for underlying disease. Comparison with prior ECGs is helpful. Abrupt axis shifts might be more significant, whereas a gradual leftward axis shift often occurs with advancing age.

Right axis deviation (RAD) and left axis deviation (LAD) were reported in 0.07% and 0.9% of military aviators (1,2). Available reports in aviators do not indicate a concern for increased likelihood of cardiac disease or events. Echocardiography to exclude structural disease is reasonable. Graded exercise testing is a consideration for the older aviator with new-onset LAD. In the absence of underlying disease, unrestricted flying without future reassessment is recommended.

First-degree Atrioventricular Block

As an isolated finding, PR interval prolongation beyond 200 ms is benign in the relatively active, healthy aviator population. It has been reported in approximately 1% of healthy aviators and is felt to be due to increased resting vagal tone. Evaluation is unnecessary for mild PR prolongation. If the PR interval is markedly prolonged, but shortens to normal or near-normal duration during exercise and the ECG is otherwise normal, unrestricted flying duties are appropriate and future reevaluation is not indicated.

Second- and Third-degree Atrioventricular Block

Healthy, young subjects often demonstrate Mobitz I (Wenckebach) atrioventricular (AV) block on 24-hour ambulatory ECG, typically during sleep. Mobitz I AV block is a rare finding on routine 12-lead ECG, reported in only 0.004% of aviator ECGs (1), and is typically considered a normal variant due to enhanced vagal tone. Mobitz II AV block, reported in 0.003% of military aviator ECGs (1), is a risk for progression to advanced and third-degree AV block with possible hemodynamic symptoms and need for permanent pacing. Many specialists would consider even asymptomatic Mobitz II AV block an indication for permanent pacing. This finding should prompt removal from all flying duties.

Third-degree AV block was reported in 0.004% of military aviator ECGs (1), including both acquired and congenital forms. Acquired third-degree AV block should be disqualified from all flying duties due to the risk of bradycardia-related hemodynamic symptoms. Most specialists would consider symptomatic or asymptomatic acquired third-degree AV block an indication for permanent pacing. Congenital third-degree AV block is a more contentious issue. There is very little experience reported for this finding in military and commercial pilots, probably because it is considered disqualifying for initial flying training and licensure. Although these individuals usually do well clinically, an increased risk of sudden death has been reported. Certification for flying duties is not recommended.

Chamber Dilation and Hypertrophy

Atrial Abnormality

Right and left atrial abnormalities were reported in only 0.004% of military aviators (1,2). These ECG findings are nonspecific in the absence of symptoms or signs of underlying disease that is expected to cause atrial enlargement or hypertrophy. In the absence of such clinical evidence of disease or of other ECG changes, evaluation is unlikely to reveal pathology. Echocardiography will suffice for assessment and disposition should be determined by any underlying disease. More likely, echocardiographywill be normal or may demonstrate only mild dilation of one or both atria without other abnormalities. This should be considered a normal variant, not requiring further assessment or any flying restriction.

Ventricular Hypertrophy

Right ventricular hypertrophy is an unusual ECG finding in an aviator population and is reflective of underlying disease. Echocardiography should be performed and further assessment and disposition guided by the findings.

Left ventricular hypertrophy (LVH) has repeatedly been shown to predict increased cardiac risk. This is especially true
if secondary ST-T wave changes are also present. Therefore, LVH voltage with associated ST-T wave changes should definitely be evaluated and appropriate medical and aeromedical disposition determined by the findings. Hypertension, aortic valve disease, and hypertrophic cardiomyopathy (HCM) would be considerations.

In the aviator population, LVH will more often be present as increased QRS voltage alone, without other ECG signs. Echocardiography will demonstrate whether LVH is truly present. If not present, no further assessment or future reassessment would seem warranted. If LVH is present, physiologic changes due to physical conditioning must be differentiated from a disease process. This is further discussed at the end of this ECG disposition section under Athletic Heart versus Cardiac Pathology.

Ectopy—Premature Supraventricular and Ventricular Contractions

Premature supraventricular contractions (PSVCs) include atrial and junctional premature beats. The prevalence of PSVC on ECG in military aviators is less than 1% (1). PSVCs are generally felt to be benign, even when frequent or paired (couplets) and not indicative of underlying disease. In USAF aviators, asymptomatic frequent and paired PSVCs have not been predictive of arrhythmic events or sustained supraventricular tachyarrhythmias (1). When very frequent and paired, PSVCs may be associated with mild symptoms. The aeromedical disposition would then be guided by the symptomatology.

Prevalence of premature ventricular contractions (PVCs) on ECG is also less than 1% in military aviators (1). Frequency and complexity of PVCs increase with advancing age, as does the prevalence of CAD and hypertension. Also, PVCs associated with some cardiac disorders are predictive of an increased risk of adverse cardiac events. Investigation for PVCs may therefore be more appropriate than for PSVCs. However, in USAF aviators, frequent and paired PVCs have not been predictive of sustained ventricular tachycardia (VT) or arrhythmic events, in the absence of underlying cardiac disease (3).

A single PSVC or PVC on an ECG may not warrant evaluation. It may be prudent to evaluate a single PVC in the older aviator and two or more ectopic beats regardless of age. Twenty-four hour ambulatory ECG will quantitate the frequency of isolated ectopy and will document any pairing or tachycardias. The frequency and complexity of ectopy should then guide further assessment (e.g., graded exercise test, echocardiography) as well as aeromedical disposition.

The USAF currently grades ectopy as a percentage of total beats on the 24-hour ambulatory recording. Rare and occasional ectopy (1% or less of total beats) is not further evaluated. Frequent ectopy (>1% up to 10% of total beats) is evaluated with echocardiography and graded exercise testing; one to ten pairs (couplets) per ambulatory recording is similarly evaluated. Very frequent ectopy (>10% of total beats) and frequent pairs (>10 pairs per ambulatory recording) are evaluated more thoroughly for underlying heart disease at a central facility. However, the significance of frequent ectopy and pairing is yet to be well defined.

Prolonged QT Interval

Prolonged QT interval may be due to primary congenital syndromes or acquired secondary to a wide variety of causes. Secondary causes must be excluded by careful history. The most common secondary cause is medication. Additional secondary causes include certain electrolyte imbalances (e.g., hypocalcemia), endocrine abnormalities, neurologic events, and nutritional deficiencies (e.g., associated with chronic alcohol abuse). Congenital long QT syndrome (LQTS) involves many genetically distinct mutations of cardiac ion channels that affect the action potential, causing susceptibility to VT. Currently, several genotypes are described. Inheritance is usually autosomal dominant, but with variable expression. Routine genetic testing for diagnosis is not yet available.

LQTS is essentially an ECG diagnosis. Other factors, primarily symptoms in the patient or relatives, are also helpful for diagnosis. QT interval varies with age, gender, and heart rate and is typically expressed as QTc (QT corrected for heart rate). Normal QTc is usually reported as 440 or less overall. For adult females, QTc greater than 460 is abnormal and QTc greater than 480 is essentially diagnostic. And for adult males, QTc greater than 450 is abnormal and QTc greater than 470 is essentially diagnostic. T-wave changes may also be present and characteristic for specific genotypes of LQTS. A patient may have only a borderline prolonged QTc or even, at times, a normal QTc and still have the LQTS syndrome.

Ambulatory ECG monitoring may demonstrate prolonged QTc and transient T-wave changes at different heart rates. The lethal arrhythmia is polymorphic VT (torsade de pointes), but short runs of VT are rarely documented on ambulatory monitoring. Exercise or startle often elicits the arrhythmia, yet it is rarely precipitated by exercise testing. Treadmill testing may help with the diagnosis—QT interval normally shortens during exercise and does not prolong during recovery. With at least some LQTS genotypes, QT interval may prolong significantly during the recovery phase. Electrophysiologic testing, signal-averaged ECG, and other sophisticated tests have not been helpful for diagnosing LQTS or predicting events.

A low-risk subset of LQTS includes subjects with LQTS by ECG and other studies, but no personal or family history of documented or suspected arrhythmic events. Annual event rate for sudden cardiac death or syncope is approximately 0.5% per year. Higher-risk subjects with a positive personal or family history of events have an approximately 5% per year risk of sudden death or syncope and 10% to 20% of first events are sudden death. Presumably, there is also a risk of presyncope and lightheadedness, although rates for these events are not well documented.

Symptoms are often provoked by exertion or startle situations. Other than recommending against competitive athletics, unrestricted activity is generally recommended for asymptomatic subjects, especially if on prophylactic
β-blocker therapy. Even symptomatic subjects, whose symptoms are controlled by β-blockers and who have a benign ambulatory ECG recording and treadmill, are generally not activity restricted except from competitive athletics. Aeromedical disposition of LQTS must consider the above risk of arrhythmic events and activity restrictions, particularly with the military aviator, for whom periodic physical fitness testing and other physical activity are often mandatory. These risks probably warrant disqualification from entry into initial flying training. If discovered in an older aviator, who has had no prior events and a negative family history, return to some restricted, low-performance flying duties may be a consideration. For pilots, this should include restriction to multipilot aircraft.

Possible Myocardial Ischemia and Infarction

ECG changes diagnostic for myocardial infarction (MI) should prompt removal from flying duties pending further diagnostic and prognostic evaluation, with disposition determined by the findings. A more common situation will be nondiagnostic changes suggesting a possible MI, such as small Q waves in the inferior limb leads or poor R-wave progression in the anterior precordial leads. Comparison with prior ECGs and repeat ECG with careful lead placement may be valuable. If further assessment is warranted, graded exercise testing alone is not adequate because it may be normal if there is no post-MI residual ischemia. More appropriate would be assessment for regional wall motion abnormalities by echocardiography or a perfusion defect by nuclear imaging. A more thorough evaluation would assess for both MI and residual ischemia either by exercise nuclear imaging or stress echocardiography.

Nonspecific ST-T wave changes can be a dilemma. They do have some predictive value for underlying disease, especially if new compared to prior tracings. However, they are also very nonspecific and the likelihood of significant disease in an otherwise healthy, active and asymptomatic aviator is low. Nonfasting condition can cause transient ST-T wave changes. If the changes persist on a repeat, fasting ECG and are new compared to prior tracings, then screening for CAD may be warranted for the older male aviator (e.g., age 35-45 years) and the postmenopausal female aviator. Younger males with high-risk profiles may also be considered for screening. Graded exercise testing is recommended.

Wolff-Parkinson-White Electrocardiographic Pattern

Wolff-Parkinson-White (WPW) ECG pattern is the classic ECG finding of short PR interval and delta wave without documented or suspected tachyarrhythmias. WPW syndrome is the ECG pattern plus tachyarrhythmia, especially supraventricular tachycardia (SVT). WPW ECG pattern is reported in approximately 1.5/1,000 in both the general population and military aviator populations. Risk of sudden death is 0.1% to 0.15% per year for all WPW subjects; low-risk subsets may be identifiable by electrophysiologic testing. The mechanism of sudden death is considered to be rapid SVT, which deteriorates into atrial fibrillation. If atrial fibrillation is conducted rapidly through the accessory pathway to the ventricle, ventricular fibrillation may ensue. The reported risk of SVT varies widely, but recent data from outpatient community populations and a military aviator population suggest a risk of 1% to 3% per year for at least 10 years after the initial diagnosis of the WPW ECG pattern.

Aeromedical disposition of WPW ECG pattern must consider the low risk of sudden death and the risk for SVT, especially for entry into initial flying training and for military aviation. Radiofrequency ablation will play an important role in some situations and is discussed with tachyarrhythmias in a later section.

Athletic Heart versus Cardiac Pathology

This topic is not exclusively ECG related, but often involves echocardiographic findings of mild dilation of one or more cardiac chambers or mild LVH. However, consideration is often precipitated by increased QRS voltage or other nonspecific ECG findings prompting the echocardiogram. In the absence of underlying pathology and any systolic or diastolic dysfunction, mild dilation or enlargement of one or more of the cardiac chambers is considered a normal physiologic variant, especially in a physically active, asymptomatic individual. No further assessment is recommended.

A common dilemma is mild, concentric LVH on echocardiogram, with or without accompanying LVH voltage on ECG, which may be physiologic hypertrophy or cardiac pathology. Two causes of LVH should be easily excluded or diagnosed. The echocardiogram itself should determine the presence or absence of aortic stenosis. Blood pressure checks should be performed for possible hypertension. If these two causes are excluded, the issue becomes physiologic variant due to physical conditioning versus HCM, an important distinction both medically and aeromedically. Most sources quote 11 mm as the upper limit of normal for left ventricular wall thickness. Left ventricular wall thickness is increased in competitive athletes compared to sedentary controls. Although this increase is usually within the normal range of wall thickness, it is often 12 to 13 mm but rarely exceeds 14 mm. Data from screening echocardiograms performed in military pilot applicants report wall thicknesses up to 12 mm in females and 13 mm in males (1).

In a physically active aviator without hypertension or aortic stenosis, mild, concentric left ventricular wall thickening of 12 to 13 mm may be considered a normal variant. Wall thickness of 14 mm or greater should be further evaluated. Serial echocardiography during abstinence from all exercise should differentiate physiology from disease. Physiologic hypertrophy will regress to normal wall thickness while HCM should not. The aviator must discontinue all aerobic and anaerobic exercise; merely reducing exercise will not cause regression of LVH. Regression is unlikely sooner than 4 weeks after exercise cessation. Continued flying, including high-G flying with straining maneuver, could be continued during this period of exercise cessation.
More than one monthly follow-up echocardiogram may be required. Once regression has been confirmed, the aviator may return to full exercise without requirement for future reassessment.

CORONARY ARTERY DISEASE

According to recent statistics published by the American Heart Association, CVDs, including stroke, CAD, and hypertension, continue to be the leading cause of death in the United States, accounting for more than 40% of all deaths (4). Atherosclerotic CAD is the leading cause of death in the industrialized world. Its importance as a concern for public health as well as aviation safety cannot be overstated. The World Health Organization projects that CVD will be the world’s leading cause of morbidity and mortality by 2025.

CAD can present along a continuum from stable angina to unstable angina, MI, and sudden cardiac death. The first presentation of disease can often be sudden cardiac death or MI. Stable angina may be the presenting symptom in only 25% of men, with unstable angina, MI, and sudden death comprising most of the presentations. Any of these symptoms could lead to a decrement in performance or to a catastrophic, sudden incapacitating event. In fact, one half of those who die from an MI do so within 1 hour of symptom onset (5). Sudden cardiac death has been recognized in case reports and anecdotal experience as the cause of loss of life and aircraft in both military and commercial aviation.

Our understanding of the causes and treatment of heart disease has improved dramatically, with death rates from CVD dropping 20% over the last decade. Yet, it remains the major cause of death in industrialized countries. Atherosclerotic burden has been shown to occur at an early age, and clinical events are the late phase of the disease process. Opportunities aimed at prevention should therefore start early in the preclinical state of disease and the identification of those at highest risk must be sought. Cardiology knowledge continues to rapidly evolve with better understanding about the pathobiology of atherosclerosis, identification of novel risk factors, and technologic advances. The milieu in which we operate and the data that emerge lead to great debate on how to effectively screen for CAD, when to perform screening, how to treat, and the prognosis if disease is found. The role that new treatments and detection methods will play on future aeromedical decision making is unknown.

Coronary angiography has been the gold standard for defining the presence and extent of CAD and is properly thought of as a lumenogram. Lesion severity is then defined as percent narrowing of the lumen diameter. Clinically, minimal CAD is usually graded as maximum stenosis less than 50% and significant CAD as maximum stenosis 50% or greater; these definitions will be used in this discussion. However, it must be noted that some literature define significant CAD as maximum stenosis 70% or even 75% or greater. Angiography helps define plaque burden but tells little about composition of plaque. Interestingly, the lumen may appear normal or have only “luminal irregularities” by angiography, yet have significant atheroma within the arterial wall, as detected by intravascular ultrasonography. This has led to the understanding that early in the disease process, the adventitia expands and maintains a constant lumen despite minimal or even moderate plaque within the arterial wall.

Prevalence

In the United States, it is estimated that more than 10 million people currently have symptomatic CAD with an even greater number having asymptomatic disease. Estimated age-adjusted prevalence of CAD in adults aged 20 years or older is approximately 5.5% to 9.0%, depending on gender and race/ethnicity (4). Autopsy studies of young soldiers killed in war have shown evidence of atherosclerosis, with up to 10% having significant lesions. In 1981, a study from the United Kingdom reported similar prevalence of disease between military and commercial pilots who were killed in aircraft accidents. The prevalence of significant CAD in this study was 19% with a mean age of 32 years (1). A review of autopsy studies of commercial pilots showed an age dependency of severe disease prevalence, with 0.6% in pilots younger than 40 years and 7.4% in pilots aged 50 years or older (1). Data from the Royal Air Force reported the prevalence of significant disease by autopsy in private, commercial, and military aircrew as 7% below age 30, rising to 18% at age 30 to 49, and 43% at older than 50 years. Atherosclerosis detected by intravascular ultrasonography performed on donor hearts at the time of cardiac transplantation showed an even higher prevalence, being present in one of six teenagers, one of three aged 20 to 29, and one of two or 50% between the ages of 30 and 39 (6). Aeromedically, CAD is a leading cause of disqualification or denial of licensure in both civilian and military pilots. Aviators as a whole probably have less CAD than the general population but still have a prevalence of disease that warrants concern for detection and treatment.

Pathobiology

Acute coronary events are predominantly caused by plaque rupture or erosion, which is more common in intermediate than in high-grade stenoses. In several studies, one half or more of the sites where MI subsequently occurred had stenoses less than 50%. Although events can occur due to plaque rupture at sites of nonsignificant disease, so-called vulnerable plaques, stenoses less than 50% tend to be markers for more extensive disease and therefore poorer prognosis.

The atherosclerotic process is complex and not completely understood. Two initial processes that play important roles in the initiation of atherosclerosis include lipid accumulation and oxidation, along with endothelial dysfunction, caused by coronary risk factors. The initial lesion is a fatty streak, which mainly comprises lipid-laden macrophages. “Vulnerable plaques” are characteristically composed of lipid-rich macrophages with a thin fibrous cap and have less smooth muscle than more mature plaques.

A hallmark of plaque vulnerability is inflammatory cell infiltrates. No modality currently available accurately identifies the vulnerable plaque but this is an area of intense research. Two studies, the Pathobiological Determinants of Atherosclerosis of Youth (PDAY) and the Bogalusa Heart Study, have helped confirm that the process starts in childhood and that CAD prevalence and extent increase with age. In PDAY, all of the aortas and about half of the right coronary arteries in the youngest age-group (15-19 years) had atherosclerotic lesions (7).

Risk Factors

A constellation of risk factors for coronary disease, now termed traditional or classic risk factors, were clearly delineated in the Framingham Heart Study and include age, gender, family history of premature CAD, hypertension, smoking, hypercholesterolemia, diabetes mellitus, and LVH. The INTERHEART study identified nine risk factors that accounted for 90% of the risk for MI worldwide, which included smoking, raised ApoB/ApoA1 ratio, hypertension, abdominal obesity, psychosocial factors, lack of daily consumption of fruits and vegetables, daily alcohol consumption, and lack of physical activity (8). Risk factors are often synergistic, such as occurs in the metabolic syndrome.

Other “emerging” risk factors associated with increased risk include homocysteine, lipid fractions such as lipoprotein (a) and apolipoproteins A and B, inflammatory markers such as C-reactive protein (CRP), interleukin 6, and urine microalbumin. The precise role these emerging risk factors will have in screening and risk stratification is yet to be determined, but they may help to determine who should receive more aggressive risk-factor modification.

Although a detailed discussion of all risk factors is beyond the scope of this text, information about some specific risk factors is provided in the subsequent text.

Cigarette Smoking

The evidence linking cigarette smoking to CVD is based on observational studies. Cigarette smoking has been linked to 400,000 premature deaths in the United States annually. A 1989 report from the United States’ Surgeon General presented data showing that smoking essentially doubled the incidence of CVD and increased CVD mortality by 50%. Nonsmokers exposed to second-hand smoke are also at a small, dose-related increased risk for coronary disease. Smoking accelerates the atherogenic process in both dose-and duration-dependent manners. Three smoking cessation trials in primary prevention populations demonstrated a 7% to 47% reduction in the rate of CAD events for those who stopped smoking. Smoking status should be a part of routine aviator evaluation. Appropriate counseling and smoking cessation programs should be made available.

Lipid Disorders

Lipoprotein content plays an important role in plaque development and disruption. Both genetic and environmental factors cause dyslipidemias. It is estimated that up to 90% of CAD patients have elevated low-density lipoprotein (LDL) cholesterol, with the majority having only modest elevation. High-density lipoprotein (HDL) cholesterol has an inverse relationship to CAD. In the Framingham Study, low-HDL cholesterol was a much stronger predictor of coronary risk than was increased LDL in subjects older than 50. The total cholesterol-to-HDL cholesterol ratio is the best discriminator between CAD cases and controls. In 1981, a retrospective analysis of USAF aviators examined total cholesterol-to-HDL cholesterol ratio in those who underwent coronary angiography for an abnormal treadmill test. A ratio greater than 6.0 was present in 88% of those with CAD compared to only 4% of those without CAD.

Lipoprotein subfractions may provide additional information about risk. Apolipoprotein B (ApoB) reflects total number of atherogenic lipoprotein particles (very LDL, intermediate-density LDL, LDL, and Lipoprotein[a]) and in some prospective studies it was found to be a better predictor of vascular events than LDL cholesterol. Increased ApoB and high triglyceride levels are more prevalent in patients with the metabolic syndrome and type 2 diabetes.

Lipoprotein (a) is an LDL particle in which ApoB is attached to the Apo(a) protein. Plasma levels of Lp(a) are determined by a single gene and hereditability is high. Lp(a) has been identified as a potent predictor of premature atherosclerosis in most prospective studies (9).

Metabolic Syndrome

The metabolic syndrome comprises a constellation of risk factors including abdominal obesity, dysglycemia, hypertension, and dyslipidemia (with low HDL cholesterol and elevated triglycerides). Diagnostic criteria have been developed by the National Cholesterol Education Panel Adult Treatment Panel III, the World Health Organization, and the International Diabetes Foundation. Of note, the different diagnostic criteria for abdominal obesity differ depending on racial background. The metabolic syndrome increases the risk for cardiovascular events significantly beyond that accounted for by the presence of the traditional risk factors (10) conferring an approximate twofold risk depending on the diagnostic criteria. The underlying mechanism appears to be related to insulin resistance. Risk for development of diabetes mellitus is also significantly increased in individuals with the metabolic syndrome.

Diabetes Mellitus

Diabetes mellitus is a common disorder and recent statistics show it to be increasing in prevalence. Diabetic patients are considered to be at high risk for coronary disease. Atherosclerosis accounts for 75% to 80% of all mortality in diabetic patients, with CAD as the leading culprit. Aggressive treatment of diabetic patients, and especially their other risk factors, is recommended. Military aircrew are usually excluded from aviation duties if diagnosed with diabetes requiring insulin or oral medications, which might cause hypoglycemia. In some jurisdictions, civilian aircrew with diabetes may be licensed for aviation duties. Such individuals
require more intensive screening for coronary disease. Further discussion of the approach to flying certification and diabetes, including insulin-dependent diabetes mellitus, may be found under the Endocrine section in Chapter 18 and the Pilot Health and Aeromedical Certification section in Chapter 11.

Obesity and Physical Activity

Physical inactivity is felt to increase the risk for coronary artery events about twofold. Quantifying the relationship between amount of physical activity and risk is often difficult. Many studies have shown that physical activity reduces the risk of CAD events, especially in men. The greatest cardiovascular risk reduction benefit is obtained when going from inactive to moderately active levels of physical activity, with less benefit going from moderate to extreme physical activity. Exercise improves hypertension control and leads to an elevation of HDL cholesterol. It has been estimated that running 10 mi/wk can increase HDL cholesterol by 25%. A linear relationship has been shown between body mass and mortality, although no study has specifically looked at the effect of weight loss and risk reduction. Typically, obesity is associated with other risk factors and these associations probably mediate its risk.

Family History

Although conventional risk factors explain much of the susceptibility to CAD, approximately 10% to 15% of individuals with CAD have no identifiable risk factors. Family studies in identical twins are consistent with premature CAD being strongly influenced by genetic factors (11). Among identical twins, premature cardiac death confers an eightfold increase in risk to the surviving male siblings and a 15-fold increase to female siblings. In the Framingham Offspring Study, parental cardiac disease led to an approximately twofold increase in risk (12).

Inflammatory Markers

Inflammation has been identified as a key element in the pathogenesis of atherosclerosis, and various markers of inflammation have been studied as indicators of atherosclerotic risk (13,14). These include inflammatory cytokines (e.g., interleukin-6), acute phase reactants such as CRP, with a high sensitivity assay-hs-CRP, and urinary microalbumin (e.g., creatinine-to-microalbumin ratio). Data from Women’s Health Study and multiple other prospective studies have demonstrated hs-CRP as an independent predictor of cardiac events. The utilization of hs-CRP (and other markers of inflammation) in risk assessment remains somewhat controversial, but most data support the use of hs-CRP in further stratification of individuals assessed as intermediate risk through traditional risk factors.

Risk Assessment and Risk Stratification

As part of periodic medical screening or certification medical examinations, basic risk factor information should be assessed in military aircrew and civilian license holders to allow estimation of cardiovascular risk. Risk indices have been developed in North America (e.g., Framingham Heart Study), Europe (PROCAM study), and elsewhere, which utilize major risk factors to assess global cardiovascular risk. Risk engines are available on-line or in hard copy to calculate risk (http://www.nhlbi.nih.gov/guidelines/cholesterol/; http://www.chd-taskforce.com/).

Clinical guidelines generally stratify risk as low, intermediate, or high based on Framingham risk scores of less than 10%, 10% to 19%, and 20% or greater. Risk scores may be modulated upward with other risk factors, such as diabetes (high-risk equivalent), metabolic syndrome, or with a family history of early CAD. In intermediate-risk individuals, assessment of emerging risk factors including Lp(a), hs-CRP, ApoB, and urinary albumin/creatinine ratio may help further stratify risk as higher or lower.

Primary Prevention

Military flight surgeons and civilian aerospace medicine practitioners have dual roles, which include responsibilities for medical flight certification and opportunities for preventive medical intervention. In many cases, mandatory periodic medical screening or certification represents the only interface of aircrew with the medical system. Such opportunities should be leveraged to obtain a comprehensive cardiovascular risk assessment.

Risk stratification based on risk indices such as Framingham identifies individuals at increased global risk. Such assessments can be clinically useful for identifying aircrew at intermediate or high risk who warrant immediate attention and intervention. Risk assessments can also serve as a motivation to adhere to risk-reduction therapies.

An important point is that such indices serve as models for risk assessment, but they do have limitations. Many individuals at low or intermediate 10-year risk are at high risk in the long term due to the cumulative effects of a single risk factor, which can lead to premature CAD if left untreated. This means each major risk factor deserves intervention, regardless of short-term absolute risk. Furthermore, the risk indices do not take into account newer risk factors and may therefore indeed underestimate the risk of a given individual. Preventive efforts should target each major risk factor. The centerpiece of long-term risk reduction is modification of lifestyle habits with physical activity, weight control, smoking cessation, and proper diet.

Numerous clinical trials have demonstrated the efficacy of cholesterol lowering in primary and secondary prevention. Early trials such as West of Scotland Coronary Prevention Study (WOSCOPS) and Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) demonstrated clear efficacy in primary prevention with a 30% to 40% reduction in relative risk for nonfatal MI or coronary deaths. Other trials of secondary prevention in patients with established coronary disease, for example, Scandinavian Simvastatin Survival Study (4S), Cholesterol and Recurrent Events (CARE), and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) demonstrated
the overwhelming benefit of lipid-modifying treatment in secondary prevention. When comparing primary and secondary trials, there was no significant difference in relative efficacy, only in absolute event rates (i.e., secondary prevention gives “more bang for the buck”). These trials support the role of aggressive lowering of LDL cholesterol in patients with documented CAD, along with aggressive lowering in patients with multiple risk factors or high-risk lipid profiles but without known disease. In recent secondary prevention trials (e.g., PROVE-IT), incremental benefit has been shown with intensive lipid lowering to LDL cholesterol targets less than or equal to 70 mg/dL.

All classes of lipid-lowering medications are in general compatible with flying duties. On initiation of treatment, a nonflying observation period of approximately 1 week is prudent to observe for idiosyncratic reactions. Statins and fenofibrates, particularly in combination, may cause myalgias or rarely, frank myositis. Concomitant use of antifungal drugs and macrolide antibiotics also increases the risk for myopathy. Patients should be cautioned to report any suspicious symptoms immediately, and creatinine kinase levels should be assessed if symptoms warrant. Statins and niacin may cause significant elevation of hepatic transaminases, and measurement of transaminase levels before and after initiating treatment is advised. A suggested protocol, currently used by the USAF, is to check hepatic transaminases before starting therapy, after 12 weeks of therapy, annually, and when clinically indicated. Creatine kinase could be obtained before therapy and when clinically indicated. In some jurisdictions [e.g., USAF, United States Navy (USN)], a waiver is required for certain classes of lipid-lowering medications, and some (e.g., niacin) are not allowed.

Guidelines for primary and secondary prevention have been published by several expert panels (15, 16, 17) and should be consulted for specific recommendations. A disturbing fact is that therapy is underutilized, with more than 80% not receiving therapy for secondary prevention and only 4% of primary prevention eligible patients receiving therapy (1,5). We in the medical profession are not adequately treating those who would benefit the most.

Screening for Coronary Artery Disease

The prevalence of asymptomatic CAD greatly exceeds that of established CAD. A major, often catastrophic event may be the initial presentation of coronary disease in up to half of previously asymptomatic individuals. Detection of asymptomatic CAD should facilitate initiation of more aggressive preventive measures to mitigate the risk of a major coronary event. Screening tests which detect asymptomatic CAD therefore have a dual role in prolonging and improving quality of life, and in reducing risk for occupational mishaps.

Screening tests for CAD are intended to detect flow-limiting, hemodynamically significant obstruction, or to detect the presence of coronary plaque. Tests for obstructive coronary lesions include exercise stress testing, stress nuclear perfusion imaging (NPI), and stress echocardiography. Techniques for plaque detection include tests for quantitative assessment of coronary artery calcium scores (CACS) utilizing electron beam computed tomography (EBCT), or multidetector computed tomography (MDCT). With the development of more sophisticated technology, with some limitations, CT contrast coronary angiography with MDCT provides information regarding both plaque burden and coronary lumenograms of a quality approaching conventional coronary angiography.

The utility of screening tests is related to the sensitivity and specificity of screening techniques, and to Bayes’ theorem. Test sensitivity reflects the ability of a screening test to detect the disease when present. Specificity reflects the test ability to correctly identify the absence of disease. Bayes’ theorem relates the post-test probability of the presence of disease to the prevalence in the population, or pretest probability. When the pretest probability is low, as is the overall prevalence of CAD in an aviator population, the post-test probability after a positive screening test remains low, with a low positive predictive value. Therefore, general screening of an aviator population with tests for obstructive coronary disease (stress testing, stress NPI, or stress echocardiography) is not recommended without prior risk stratification. Application of tools utilizing risk factor analysis (e.g. Framingham and other risk factors as discussed earlier) identifies individuals in whom the pretest probability is higher, and in whom secondary screening tests will have a greater utility. Individual aviation authorities must decide what level of pretest probability should trigger secondary screening testing. Generally, this is reserved for aviators identified as being at “high risk” based on risk factor analysis. However, the risk level identified for triggering secondary screening may relate not only to aviation safety but also to mission risk management, with a lower threshold, for example, in a long-duration space crewmember or a high-performance military aviator.

The choice of test for screening depends on availability, expertise, cost, and operating characteristics of the test (sensitivity, specificity). Tests with higher sensitivity will detect the disease more often when present, with fewer “false negatives.” Higher specificity will be reflected in fewer “false-positive” results. An important consideration in determining aeromedical disposition is the prognostic value of a negative screening test. A recent meta-analysis indicated that in individuals with a normal exercise NPI or stress echocardiography study, event rates for MI or cardiac death were less than 0.6% per year over the following 3 years (18). USAF data comparing exercise treadmill, thallium NPI, and cardiac fluoroscopy showed event rates 0.5% per year or less over 5 years of follow-up for all three modalities.

Stress Testing

Exercise stress testing assesses for obstructive, flow-limiting coronary artery lesions and additionally provides information about blood pressure response, arrhythmias, and aerobic capacity. It has the advantage of being both safe and widely available. The sensitivity and specificity of exercise stress
testing for hemodynamically obstructive lesions is approximately 60% to 70%; therefore, application in a population with low-disease prevalence results in large numbers of false-positive results, requiring further investigation to clarify. Sensitivity and specificity may be lower in women.

Current recommendations by an expert committee are that exercise stress testing is a Class IIb indication (reflecting conflicting evidence or divergence of opinion) in asymptomatic men older than 45 years and for women older than 55 years involved in special occupations, such as aviation, in which impairment might affect public safety (19).

In an unselected military aviator population, the positive predictive value of an abnormal stress test for significant angiographic CAD was only 10%. Preselection by abnormal resting ECG doubled the positive predictive value to approximately 20% (1). A prospective study of treadmill testing in 25,927 apparently healthy, asymptomatic men with a mean age of 43 years showed that an abnormal treadmill test had an age-adjusted relative risk for CAD of 20. This increased sequentially as the number of risk factors increased (age-adjusted relative risk of 80 with three or more risk factors). They concluded that exercise testing was a worthwhile tool to predict future risk of CAD death, especially in those with more cardiac risk factors (20).

Nuclear Testing

NPI assesses the perfusion-dependent distribution of isotopes in the myocardium at rest and after stress. NPI with an isotope such as thallium or technetium improves the sensitivity and specificity of stress testing to approximately 85% to 90%. Stress may be induced either through exercise treadmill, cycle ergometry, or pharmacologically, as with dobutamine infusion. Because of the additional cost and radiation exposure involved, NPI is generally utilized in individuals with abnormal treadmill tests or baseline ECG abnormalities that preclude diagnostic ST changes (e.g., LBBB).

Multiple gated acquisition scans (MUGA) provide information about global ventricular function (measurement of ejection fraction) and segmental wall motion abnormalities, and may complement information provided by NPI studies.

Stress Echocardiography

Stress echocardiography assesses segmental and global myocardial contractility at rest and with stress. This is assessed by imaging the myocardium and endocardium. Stress may be accomplished with an exercise treadmill, supine bicycle exercise, or pharmacologically (e.g., dobutamine infusion). Sensitivity and specificity are similar to stress NPI (21). Limitations include technical difficulties in accurate imaging of all myocardial segments, which may be improved with injection of contrast agents that opacify the ventricles. Stress echocardiography may be particularly useful in women, avoiding radiation exposure while providing a more sensitive testing modality than stress testing, which has decreased sensitivity in women. Stress echocardiography may also be useful as a follow-on screen in individuals with positive stress tests.

Tests which Assess for Coronary Plaque

With the evolution of our understanding of the pathogenesis of CAD from the initial formation of atherosclerotic plaque, progressing slowly over time to flow-limiting obstructive lesions, the detection of early plaque lesions became appealing. The presence of calcium deposition in the coronary arteries almost always reflects the presence of coronary plaque, although earlier in evolution, plaque may not be calcified.

Coronary artery fluoroscopy (CAF) has been used since the 1960s and has been relatively accurate to predict the presence of anatomic atherosclerotic disease. CAF is a nonquantitative assessment for coronary calcium. In studies by the US Army and USAF, coronary calcium detected by CAF has been shown to have a higher positive and negative predictive value for obstructive coronary disease and coronary events than exercise stress testing or stress thallium, with a sensitivity and specificity of 70% to 75% (22,23).

Coronary artery calcium can be measured quantitatively by CT scanning techniques, which are coupled with ECG gating to overcome the problem of cardiac motion during acquisition. EBCT uses an electron sweep of stationary tungsten rings that generates rapid radiographic images. Multislice computed tomography or multidetector computed tomography (MSCT/MDCT) utilizes a gantry of multiple rapidly rotating CT scanners with rapid rotation (300-400 ms). Current generation MDCTs utilize up to 64 slices, with future generations already in development. EBCT and MDCT produce similar scores, except at very low score levels. Radiation exposure with MDCT is significantly greater than EBCT.

CACS results are quantitatively expressed in Agatston units. Normative data has been established in large data sets (24). Quantitative coronary calcium scores reflect overall plaque burden and have been demonstrated in both retrospective and prospective studies to provide incremental prognostic information for coronary events beyond that acquired from standard risk data. CACSs greater than 100 are considered to represent a threshold above which coronary events are more likely, with asensitivity, specificity, and odds ratio at 89%, 77%, and 25.8%, respectively (25). However, the presence of any coronary calcium reflects the presence of coronary plaque, and in conjunction with other risk factor data may guide the intensity of preventive measures (e.g., lipid-lowering targets) and further diagnostic evaluation.

Only gold members can continue reading. Log In or Register to continue