Mitral Regurgitation / Mitral Insufficiency

Mitral regurgitation, also known as mitral insufficiency, is a cardiac condition in horses characterized by the backward flow of blood through the mitral valve during ventricular contraction. The mitral valve, located between the left atrium and left ventricle, normally prevents blood from flowing backward when the powerful left ventricle contracts to push blood into the systemic circulation. When this valve fails to close properly or becomes incompetent, blood leaks back into the left atrium with each heartbeat, reducing the efficiency of the heart's pumping action and setting the stage for progressive cardiac dysfunction.

Mitral regurgitation represents one of the most commonly diagnosed valvular abnormalities in horses, though its true prevalence in the general equine population remains difficult to determine as many cases produce no clinical signs. Studies examining athletic horses and those undergoing pre-purchase examinations suggest that some degree of mitral regurgitation may be present in 3 to 5 percent of the population, with the incidence increasing substantially in older animals. The condition affects horses of all breeds and uses, though performance horses undergo more frequent cardiac evaluation, leading to higher detection rates in these populations.

The impact of mitral regurgitation on equine health ranges from negligible to severely life-limiting depending on the degree of valvular incompetence. Mild cases may never produce clinical signs and have no effect on the horse's performance or longevity. Moderate regurgitation may reduce athletic capacity without causing obvious symptoms at rest. Severe mitral insufficiency leads to progressive enlargement of the left-sided cardiac chambers, development of congestive heart failure, exercise intolerance, and potentially sudden cardiac death during exertion. The welfare implications and safety concerns associated with this condition make accurate diagnosis and ongoing monitoring essential.

While mitral regurgitation cannot be cured or surgically corrected in horses as it can in humans and small animals, many affected horses can be managed successfully for extended periods with appropriate care. Medical therapy can help control symptoms of heart failure when they develop, and exercise recommendations can reduce the risk of sudden death. Early detection through careful auscultation and echocardiographic examination allows appropriate management decisions and helps protect both the horse and any riders. Understanding the progressive nature of this condition enables owners and veterinarians to make informed decisions about the horse's career and care throughout its life.

The primary causes of mitral regurgitation in horses involve structural abnormalities of the valve apparatus that prevent proper closure during ventricular contraction. Degenerative changes affecting the valve leaflets represent the most common cause, with progressive thickening, fibrosis, and nodular changes gradually impairing the valve's ability to seal effectively. The valve leaflets may become irregular in shape and texture, preventing the precise contact necessary for complete closure. Additionally, the chordae tendineae, the fibrous cords that anchor the valve leaflets to the ventricular wall and prevent prolapse, may elongate, rupture, or become fibrotic, contributing to valvular dysfunction.

Genetic and breed predispositions to mitral regurgitation have been suggested though not definitively established in horses as they have been in some other species. Certain families of horses appear to show higher rates of valvular degeneration, suggesting possible hereditary influences on valve structure or durability. Thoroughbreds and related breeds may face somewhat elevated risk, though whether this reflects true genetic susceptibility or simply higher rates of detection due to frequent cardiac evaluation in these performance populations remains unclear. The age-related nature of most cases suggests cumulative stress on the valve structure over time rather than simple inherited malformation in most affected horses.

Environmental and management factors can contribute to the development or worsening of mitral regurgitation. Horses subjected to intense athletic training over many years experience repeated cardiac stress that may accelerate degenerative changes in the valve apparatus. The constant hemodynamic demands of high-level performance require sustained valvular function under challenging conditions. Nutritional factors affecting cardiac muscle and connective tissue health may influence valve durability, though specific dietary relationships have not been established. Infectious endocarditis, though relatively rare in horses, can directly damage the mitral valve and cause acute regurgitation of variable severity.

Risk factors for developing mitral regurgitation include advancing age, which remains the most significant predictor of valve degeneration. Horses over 15 years of age show markedly higher prevalence of mitral insufficiency compared to younger animals. The cumulative effects of millions of cardiac cycles gradually wear on the valve structures. Prior episodes of endocarditis may leave residual valve damage even after infection resolves. Systemic hypertension, though uncommon in horses, increases the pressure load against which the valve must close. Concurrent aortic regurgitation increases volume load on the left ventricle and may accelerate mitral valve deterioration. Dilated cardiomyopathy can cause secondary mitral regurgitation through ventricular remodeling.

The pathophysiology of mitral regurgitation involves progressive adaptation and eventual failure of compensatory mechanisms. When the valve becomes incompetent, blood flows backward into the left atrium during ventricular systole, reducing forward cardiac output. Initially, the left atrium dilates to accommodate this additional volume, maintaining relatively normal pressures. The left ventricle also dilates to handle the increased total volume it must manage each cycle. These compensatory changes may maintain adequate cardiac function for extended periods, particularly if the regurgitation develops gradually. However, continued progression eventually overwhelms compensatory capacity, leading to elevated left atrial pressure, pulmonary congestion, and ultimately congestive heart failure with clinical signs of exercise intolerance, respiratory difficulty, and potentially fatal decompensation.

Early warning signs of mitral regurgitation may be extremely subtle or entirely absent, making proactive screening important for at-risk horses. Because horses are prey animals that instinctively mask signs of weakness, early cardiac dysfunction often goes unnoticed. The most consistent early finding is a heart murmur detected during routine veterinary examination or pre-purchase evaluation. Owners might notice subtle changes in exercise tolerance, such as slightly slower recovery after work or mild reluctance to maintain effort during demanding activities. Very perceptive owners may detect occasional mild coughing, though this sign is often attributed to respiratory causes rather than cardiac dysfunction.

As mitral regurgitation progresses, more recognizable symptoms develop. Exercise intolerance becomes more apparent, with the horse unable to maintain previously achievable performance levels. The horse may fatigue more quickly during work, require longer rest periods, or show reluctance to engage in strenuous activity. Respiratory rate may remain elevated after exercise longer than expected. Some horses develop a soft, chronic cough, particularly noticeable during or after exercise when increased cardiac demand exacerbates the regurgitation. Mild ventral edema may develop, beginning around the lower chest and abdomen.

Behavioral changes accompany the progression of mitral regurgitation as the horse experiences the effects of reduced cardiac output. Affected horses may show decreased appetite and gradual weight loss despite adequate nutrition. Depression and reduced interaction with handlers or herd mates may become apparent. The horse may seek rest more frequently and resist engaging in activities it previously enjoyed. Changes in drinking behavior may occur, with some horses drinking more while others show reduced water intake. Sleep patterns may change, with more time spent in recumbent rest positions.

Physical signs of advanced mitral regurgitation include visible manifestations of congestive heart failure. Peripheral edema develops in dependent areas including the ventral abdomen, sheath or udder, and lower limbs. Jugular venous distension or pulsation may become visible. The respiratory rate increases even at rest, and lung sounds may reveal crackles indicating pulmonary edema. The heart rate may be elevated and irregular if secondary arrhythmias have developed. The mucous membranes may appear pale or congested depending on the state of cardiac output and venous pressure. Weight loss becomes pronounced as the demands of heart failure exceed nutritional intake.

The progression of symptoms in mitral regurgitation typically follows a predictable course over months to years. Many horses remain stable with minimal signs for extended periods, particularly if the condition develops gradually and compensatory mechanisms keep pace. Eventually, however, the compensatory capacity of the heart is exceeded, and decompensation occurs with relatively rapid worsening of clinical signs. The transition from compensated to decompensated heart failure may be triggered by additional stress such as concurrent illness, increased workload, or progression of the underlying valve disease. Once heart failure develops, symptoms typically worsen progressively without treatment.

Emergency symptoms requiring immediate veterinary attention include sudden collapse or profound weakness during exercise, which may indicate cardiac arrhythmia or acute decompensation. Severe respiratory distress with rapid, labored breathing suggests pulmonary edema and constitutes a life-threatening emergency. Marked generalized edema developing rapidly indicates acute cardiac decompensation. Blue or purple discoloration of the mucous membranes signals inadequate blood oxygenation. Any horse with known mitral regurgitation that suddenly deteriorates deserves immediate veterinary evaluation. Sudden death during exercise, unfortunately, may be the first sign of severe mitral regurgitation in some horses that had not been previously diagnosed.

The diagnostic process for mitral regurgitation begins with careful physical examination, particularly thorough cardiac auscultation by a licensed equine veterinarian. The hallmark finding is a systolic heart murmur, meaning a sound heard during the contraction phase of the cardiac cycle when blood is regurgitating backward through the incompetent valve. This murmur is typically best heard over the left side of the chest in the mitral valve area, which lies approximately at the level of the elbow. The character of the murmur, including its loudness, quality, and radiation pattern, provides initial information about severity, though auscultation alone cannot reliably predict clinical significance. Physical examination also assesses for signs of heart failure including edema, jugular distension, and abnormal lung sounds.

Diagnostic testing following detection of a murmur aims to characterize the severity and significance of the regurgitation. Echocardiography represents the gold standard for evaluating mitral regurgitation, allowing direct visualization of valve structure and function, measurement of regurgitant jet size and characteristics, and assessment of cardiac chamber dimensions. Color flow Doppler imaging shows the pattern and extent of backward blood flow through the valve. M-mode and two-dimensional imaging measure left atrial and ventricular dimensions, with enlargement indicating hemodynamic significance. Electrocardiography identifies any concurrent arrhythmias that may complicate the clinical picture. Blood work generally remains normal unless other conditions coexist.

Advanced diagnostic procedures may be necessary to fully characterize complex cases or establish prognosis for athletic horses. Exercise echocardiography or electrocardiography evaluates cardiac function and rhythm during actual work, potentially revealing abnormalities not apparent at rest. Standardized exercise testing with heart rate monitoring assesses cardiovascular response to increasing workload. Twenty-four-hour Holter monitoring detects intermittent arrhythmias that might pose risk during exertion. Cardiac biomarkers including cardiac troponin I may indicate myocardial stress or damage. In research settings, cardiac catheterization can directly measure intracardiac pressures, though this invasive technique is rarely performed in clinical practice.

Differential diagnosis for mitral regurgitation includes other causes of cardiac murmurs and other explanations for clinical signs such as exercise intolerance. Functional or flow murmurs occur in normal hearts under certain conditions such as anemia, excitement, or athletic conditioning and must be distinguished from pathological regurgitation. Aortic regurgitation produces a diastolic murmur with a different character and location. Tricuspid regurgitation may coexist with or be mistaken for mitral valve disease. Ventricular septal defects cause systolic murmurs that may sound similar on auscultation. Endocarditis can cause regurgitation with additional systemic signs of infection. Careful echocardiographic examination definitively identifies the source and nature of any murmur and distinguishes clinically significant regurgitation from incidental findings.

Treatment of mitral regurgitation focuses on medical management since surgical valve repair or replacement is not currently feasible in horses. For horses with mild regurgitation and no clinical signs, no specific treatment is required beyond appropriate monitoring and exercise guidelines. These horses may continue their normal activities with periodic echocardiographic reevaluation to detect progression. When significant regurgitation is present, activity modification becomes important to reduce cardiac demand and minimize the risk of sudden death during exertion. Recommendations regarding exercise level should be individualized based on the degree of regurgitation, presence of chamber enlargement, arrhythmia status, and the horse's intended use.

Medical management becomes necessary when signs of congestive heart failure develop. Diuretic therapy with furosemide forms the cornerstone of treatment, reducing fluid accumulation in the lungs and peripheral tissues by promoting urinary fluid excretion. Dosing must be carefully balanced to relieve congestion without causing excessive dehydration and electrolyte disturbances. Angiotensin-converting enzyme inhibitors may be added to reduce cardiac workload by dilating blood vessels and decreasing the volume work of the heart. Digoxin may be used cautiously to improve cardiac contractility and help control heart rate, particularly when atrial fibrillation has developed as a secondary complication.

Management of secondary arrhythmias often becomes necessary as mitral regurgitation progresses. Atrial fibrillation commonly develops due to atrial dilation and may require specific treatment. Quinidine has traditionally been used to convert atrial fibrillation to normal rhythm, though its use in horses with significant structural heart disease carries increased risk. Rate control using digoxin or calcium channel blockers may be preferable to rhythm control in some cases. Ventricular arrhythmias require careful evaluation and may be treated with lidocaine in acute situations or oral antiarrhythmic drugs for chronic management. Any antiarrhythmic therapy in horses with heart disease requires close monitoring.

Supportive care measures complement specific cardiac therapy and help maintain quality of life. Nutritional management should maintain appropriate body condition without excessive weight that increases cardiac workload. Low-sodium diets may help reduce fluid retention, though severe sodium restriction is difficult to achieve in horses and may cause palatability issues. Access to salt should be limited in horses receiving diuretic therapy. Small, frequent meals may be better tolerated than large volumes of feed. Adequate water access is essential, though monitoring intake helps assess diuretic response. Comfortable housing with protection from temperature extremes reduces metabolic demands.

Exercise modification is a critical component of managing mitral regurgitation at any stage. For horses with mild to moderate regurgitation without failure, light to moderate exercise may actually be beneficial for maintaining cardiovascular fitness, though high-intensity work and activities involving maximal exertion should be avoided due to the risk of sudden death. Horses with significant regurgitation should not be ridden due to safety concerns for the rider. Turnout in small paddocks allows for gentle self-exercise. As heart failure develops, even voluntary activity may need to be restricted. Individual recommendations depend on echocardiographic findings and should be revisited as the condition evolves.

Treatment decisions are influenced by multiple factors including clinical stage, the horse's age and intended use, and owner goals. Horses used for breeding or light pleasure may continue for extended periods with mild regurgitation. Competition horses with significant regurgitation face difficult decisions about career termination for their safety and that of their riders. Financial considerations affect the feasibility of long-term medical management. Quality of life assessment should guide all treatment decisions, with recognition that heart failure in horses is ultimately progressive despite therapy. Humane euthanasia becomes appropriate when clinical signs can no longer be adequately controlled or when quality of life deteriorates significantly.

The concept of recovery from mitral regurgitation differs from that of many other conditions because this is typically a progressive, irreversible condition rather than one from which horses recover in the traditional sense. The timeline for horses with mitral regurgitation involves management of a chronic disease rather than recovery from an acute illness. Horses with mild regurgitation may remain stable for many years with minimal or no progression. Those with moderate regurgitation typically show gradual worsening over months to years, with the rate of progression varying considerably between individuals. Once heart failure develops, the timeline becomes more compressed, though appropriate treatment can provide meaningful extension of comfortable life.

Post-diagnosis care and monitoring form the cornerstone of long-term management. Regular veterinary evaluation including cardiac auscultation should occur every six to twelve months for stable cases, with more frequent assessment if changes occur. Periodic echocardiographic examination, typically annually for moderate cases or whenever clinical changes are noted, tracks progression by monitoring chamber dimensions and regurgitation severity. Electrocardiographic monitoring helps detect developing arrhythmias. Owners should be educated to recognize early signs of heart failure including exercise intolerance, respiratory changes, coughing, and edema, prompting veterinary evaluation when these develop.

Prognosis for horses with mitral regurgitation depends on multiple factors. Mild regurgitation with no chamber enlargement carries an excellent prognosis, with many horses living normal lifespans without limitation. Moderate regurgitation with compensated chamber enlargement suggests reduced long-term prognosis but often allows continued useful life for several years. The development of heart failure marks a significant prognostic inflection point, with median survival times measured in months rather than years even with appropriate treatment. The presence of atrial fibrillation generally worsens prognosis. The rate of progression, response to therapy, and maintenance of quality of life ultimately determine individual outcomes.

Long-term outlook for horses with mitral regurgitation requires realistic expectations and appropriate planning. Career expectations must be adjusted based on disease severity, with severely affected horses retiring from riding for safety reasons. Quality of life can often be maintained for extended periods with appropriate management and medical treatment. Owners should be prepared for the eventual progression of disease and the need for humane euthanasia when quality of life can no longer be maintained. Planning ahead for end-of-life decisions reduces stress when the time comes. Despite the progressive nature of this condition, many horses with mitral regurgitation enjoy comfortable lives for years following diagnosis with attentive care.

Prevention of mitral regurgitation is limited because the underlying degenerative processes that typically cause this condition are not fully understood and may involve aging processes and individual susceptibility factors that cannot be modified. However, certain management practices may help maintain cardiac health and potentially slow progression in affected horses. Avoiding extreme athletic demands in young horses may preserve cardiac structure by reducing cumulative stress on the valve apparatus. Appropriate conditioning programs that build cardiovascular fitness gradually rather than through abrupt increases in training intensity support overall cardiac health. Recognition that the equine heart, like the human heart, has limits helps guide sensible training approaches.

Nutritional considerations for cardiac health focus on maintaining overall fitness and avoiding conditions that stress the cardiovascular system. Balanced nutrition appropriate for the horse's life stage and activity level supports all body systems including the heart. Maintenance of appropriate body weight reduces cardiovascular workload compared to carrying excess weight. Adequate vitamin E and selenium support cardiac muscle function. Avoidance of ionophore toxicity through careful feed management is essential, as ionophore poisoning can cause severe cardiac damage including valve abnormalities. Clean water access and appropriate electrolyte balance support normal cardiac function.

Exercise and conditioning guidelines for maintaining cardiac health emphasize graduated training approaches and appropriate recovery time. Building cardiovascular fitness through progressive increases in training intensity allows adaptive changes in cardiac structure without overwhelming compensatory mechanisms. Adequate warm-up before intense exercise and cool-down afterward support normal cardiovascular responses. Monitoring recovery parameters such as heart rate return to baseline helps identify horses that may be experiencing excessive cardiovascular stress. Age-appropriate activity levels recognize that older horses may not tolerate the same demands as younger animals.

Environmental factors affecting cardiac health in horses include temperature and humidity extremes that increase cardiovascular demand. Providing appropriate shelter and avoiding work during extreme conditions reduces cardiac stress. Air quality and respiratory health indirectly affect the heart through their influence on pulmonary function. Stabling conditions that minimize respiratory irritants support overall cardiopulmonary health. Stress management through appropriate herd dynamics and handling practices reduces unnecessary cardiovascular activation. Regular exercise access supports cardiovascular fitness better than prolonged stall rest.

While vaccination and deworming do not directly prevent mitral regurgitation, they contribute to prevention of conditions that can cause secondary cardiac damage. Vaccination against Streptococcus equi helps prevent strangles, a bacterial infection that can occasionally lead to endocarditis and valve damage. Control of parasites that can cause inflammatory conditions reduces systemic stressors. Prevention of influenza and other viral infections avoids myocarditis that can affect overall cardiac function. Regular dental care ensures proper nutrition to support all body systems. Comprehensive preventive care maintains overall health that supports cardiovascular function throughout the horse's life.

Daily management adjustments for horses with mitral regurgitation depend on the severity of the condition and presence of clinical signs. Horses with mild, asymptomatic regurgitation may require no changes to their daily routine beyond scheduled monitoring. Those with more significant disease benefit from modifications that reduce cardiac workload and stress. Feeding multiple smaller meals throughout the day rather than large volumes at once reduces the metabolic demands associated with digestion. Hay should be provided in elevated feeders to avoid extended periods with the head down, which can exacerbate respiratory signs if pulmonary congestion is present. Calm, predictable handling routines minimize stress-related cardiovascular demands.

Housing and turnout considerations for horses with mitral regurgitation balance the benefits of exercise against the risks of overexertion. Small paddock turnout allows for gentle self-exercise that supports cardiovascular fitness without the risk of high-intensity exertion that might occur in larger fields or with active companions. Turnout companions should be chosen carefully to avoid rough play. Shelter access protects against temperature extremes that increase cardiovascular demand. Stabling during severe weather may be appropriate. Footing should be even and safe to prevent falls that could cause injury to a horse with reduced exercise tolerance. Access to water and salt should be appropriate to the horse's treatment regimen.

Exercise modifications for horses with mitral regurgitation must be individualized based on disease severity and clinical status. Horses with mild regurgitation and no chamber enlargement may continue light to moderate riding with periodic reevaluation, avoiding maximal exertion and competitive activities. Those with significant regurgitation should not be ridden for safety reasons, as sudden decompensation during work poses risks to both horse and rider. Hand-walking provides beneficial exercise for horses that can no longer be ridden. Turnout provides gentle exercise appropriate for horses in heart failure. Complete stall rest is rarely indicated and may actually be counterproductive for maintaining overall fitness and mental well-being.

Monitoring and ongoing care requirements increase as mitral regurgitation progresses. Owners should check daily for signs of fluid accumulation including leg swelling and ventral edema. Respiratory rate at rest should be observed, with increases suggesting possible pulmonary congestion. Appetite and water intake monitoring helps track overall condition. Medication administration must be consistent if the horse is receiving cardiac drugs. Weight monitoring helps track nutritional status and fluid balance. Regular communication with the veterinarian about any changes ensures timely adjustment of treatment. Records of observations help identify trends over time.

Quality of life and use considerations for horses with mitral regurgitation require honest assessment and realistic expectations. Many horses with mild to moderate regurgitation enjoy excellent quality of life for years with appropriate management. Retirement from performance activities does not preclude a fulfilling life as a companion or light pleasure horse in many cases. As the condition progresses, quality of life assessment becomes increasingly important. Signs of good quality of life include normal appetite, comfortable breathing, ability to move freely without distress, and engagement with the environment and companions. When these parameters deteriorate despite appropriate treatment, humane euthanasia should be considered to prevent suffering.

Thoroughbreds appear to have somewhat elevated rates of mitral regurgitation detected on cardiac examination compared to some other breeds, though whether this represents true genetic susceptibility or reflects detection bias from more frequent cardiac evaluation in this athletic breed remains uncertain. The intense cardiovascular demands of racing may contribute to valve wear over time, making careful cardiac screening particularly important in this population. Related breeds including Standardbreds and their crosses may share similar risk profiles. The widespread use of Thoroughbreds in the development of modern sport horse breeds means any genetic predisposition could potentially be distributed across multiple related populations.

Breed-related use patterns influence the clinical significance and detection of mitral regurgitation more than breed identity per se affects disease risk. Sport horses and upper-level competition horses undergo frequent veterinary examination including cardiac evaluation, leading to higher detection rates. Racing breeds experience detection during regulatory pre-race examinations. Draft breeds may have disease go undetected longer due to less intensive monitoring and lower performance demands that might reveal early symptoms. Stock horses in regular work receive varied levels of cardiac screening. All breeds benefit from thorough auscultation during routine veterinary visits, as early detection allows appropriate management decisions regardless of breed.

Genetic testing is not currently available for predisposition to mitral regurgitation in horses, as the specific genetic factors involved have not been identified. Breeding decisions therefore cannot be based on genetic screening. However, horses with significant mitral regurgitation might reasonably be excluded from breeding programs on the principle of avoiding propagation of potentially heritable susceptibility, particularly if multiple related horses are affected. Pre-breeding cardiac examination including echocardiography provides baseline information. Awareness that mitral regurgitation tends to develop later in life means that young breeding horses may not yet have manifested a condition they could potentially pass to offspring. The multifactorial nature of most cases complicates breeding recommendations significantly.

Several conditions commonly co-occur with mitral regurgitation, reflecting shared underlying mechanisms or physiological relationships. Aortic regurgitation frequently accompanies mitral valve disease, as similar degenerative processes affect both valves. Horses with multi-valve involvement generally have a worse prognosis than those with isolated mitral regurgitation. Atrial fibrillation commonly develops as a consequence of left atrial enlargement caused by mitral regurgitation, and its presence complicates management and worsens outlook. Congestive heart failure represents the end stage of progressive mitral regurgitation when compensatory mechanisms are exhausted. Pulmonary hypertension may develop secondary to chronically elevated left atrial pressure. Recognition of these associated conditions helps guide comprehensive management.

Conditions presenting with similar clinical signs to mitral regurgitation require differentiation for appropriate treatment. Other causes of heart murmurs including tricuspid regurgitation, ventricular septal defects, and functional flow murmurs may be detected on auscultation. Exercise intolerance has many potential causes beyond cardiac disease, including respiratory conditions, musculoskeletal pain, anemia, and systemic illness. Ventral edema can result from hypoproteinemia, venous obstruction, or other causes independent of heart failure. Coughing has numerous respiratory and cardiac causes. Thorough diagnostic workup including echocardiography definitively identifies the source of murmurs and helps distinguish cardiac from non-cardiac causes of clinical signs.

Potential complications of mitral regurgitation extend the impact of the primary valve disease. Atrial fibrillation significantly complicates the clinical picture by reducing cardiac output and increasing the risk of thromboembolism. Pulmonary edema develops as left atrial pressure rises and fluid accumulates in the lungs, causing respiratory distress. Pleural effusion may accompany pulmonary congestion. Sudden death during exercise remains a significant concern, particularly in horses with moderate to severe regurgitation that continue athletic activity. Chronic heart failure leads to progressive debilitation, weight loss, and deteriorating quality of life despite treatment. Secondary renal dysfunction can develop from reduced cardiac output and diuretic therapy. Understanding these potential complications prepares owners for the possible trajectory of disease.