Special Considerations (Drugs, Pregnancy, Noncardiac Surgery, Anticoagulation, Valve-related Tumors)
Ellen Mayer Sabik
I. DRUG-INDUCED VALVE DISEASE
The concept of drug-induced valvular heart disease first surfaced in the mid-1960s when patients taking ergot alkaloids for migraine prophylaxis developed valvular regurgitation. This idea was later strengthened in the late 1990s by the development of valvular disease in patients taking the appetite suppressants fenfluramine and dexfenfluramine. More recent medications shown to cause valvular heart disease include ergot-derived dopamine agonists used for the treatment of Parkinson disease (pergolide) and those used to treat hyperprolactinemic patients (cabergoline). The most recent additions to the list include MDMA (3,4-methylenedioxymethamphetamine), otherwise known as the recreational drug ecstasy, and benfluorex, used to treat overweight diabetics. All of these drugs (see Table 10.1) share a common pharmacologic action on the 5-hydroxytryptamine 2B (5-HT2B) receptor (a specific serotonin receptor), which is responsible for the development of valvular disease. It is important to note that this “off-target effect” results in pathologic changes on the valves because the 5-HT2B receptors are expressed in high concentrations on the valve leaflets.
A. Histopathology of drug-induced valve disease. To understand the development of valvular disease caused by the above agents, one must first look at the structure and functional histology of the cardiac valves. The cardiac valves and their supporting structures serve to maintain unidirectional blood flow throughout the cardiac chambers.
1. Human semilunar valves are lined with endothelium and have three well-defined tissue layers, each with its own role or function: (1) ventricularis—provides elasticity when leaflet changes shape (made of collagen and elastic fibers), (2) spongiosa—cushions for physical forces (made of loose collagen and proteoglycans), and (3) fibrosa—provides strength (made of collagen).
2. Atrioventricular valves have analogous layers with similar components: (1) atrialis, (2) spongiosa fibrosa, and (3) ventricularis.
3. There are two types of cells present in heart valves, including valvular endothelial cells covering the leaflet surfaces and valvular interstitial cells. The valvular interstitial cells are the most prevalent cells within the valves and are responsible for maintaining the integrity of the valve tissue and regular repair following valve injury. These cells maintain the integrity of the valve by maintaining the extracellular matrix, which is composed of proteoglycans, collagens, and elastin. Heart valve pathology arises when there are changes to the extracellular matrix. This occurs in myxomatous valve disease in addition to drug-induced valvulopathies.
There are several different 5-HT receptors; however, only 5-HT2B receptor has been implicated in the development of valvular disease because of its high concentration in human heart valves and pulmonary arteries (PAs). Agonists of the
5-HT2B receptor appear to have direct mitogenic effects on the vascular interstitial cells, causing proliferation of fibroblasts and smooth muscle cells and upregulation of transforming growth factor β, stimulating glucosaminoglycan production. The pathologic findings in these patients are similar to those found in patients with carcinoid heart disease in which the enterochromaffin cells produce high levels of serotonin, with tissue thickening caused by excess extracellular matrix, made up of glycosaminoglycans and collagen, but no significant inflammation and little calcium. It is clear from all of these drugs that have been shown to cause a valvulopathy that the mechanism of this process is 5-HT2B receptor agonism, and future drugs (and metabolites) being developed should be tested for this activity before being used in large clinical trials.
5-HT2B receptor appear to have direct mitogenic effects on the vascular interstitial cells, causing proliferation of fibroblasts and smooth muscle cells and upregulation of transforming growth factor β, stimulating glucosaminoglycan production. The pathologic findings in these patients are similar to those found in patients with carcinoid heart disease in which the enterochromaffin cells produce high levels of serotonin, with tissue thickening caused by excess extracellular matrix, made up of glycosaminoglycans and collagen, but no significant inflammation and little calcium. It is clear from all of these drugs that have been shown to cause a valvulopathy that the mechanism of this process is 5-HT2B receptor agonism, and future drugs (and metabolites) being developed should be tested for this activity before being used in large clinical trials.
TABLE 10.1 Medications That Cause Valvular Heart Disease | ||||||||||||||||||||||||
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B. Echocardiographic features of drug-induced valvular disease
1. In order to screen a patient for the development of drug-induced valvulopathy, there must be a high clinical index of suspicion for the clinician ordering a transthoracic echocardiogram. It is often difficult to prove a causal relationship in an individual patient because typically there is no pretreatment baseline echocardiogram.
2. Typical features include mild or moderate leaflet thickening without calcification or commissural fusion (a hallmark of rheumatic valve disease). The leaflets appear “furled” or restricted, with the restricted leaflet closure causing the regurgitant lesions. The shortening and thickening of the subvalvular apparatus (especially chordae) appear to be out of proportion to the thickening of the leaflets, and the posterior leaflet is typically more affected than the anterior. When the aortic valve is involved, there is typically centrally originating aortic regurgitation (AR) due to restricted leaflet closure with only mild leaflet thickening. The tricuspid valve appears to be less commonly involved than the mitral and aortic valves.
C. Valvular heart disease associated with specific drugs
1. Migraine drugs. These are the oldest drugs recognized to have a potential link with valvular disease. Both are still in use, but only for short-term treatment.
a. Methylsergide—induces fibrotic tissue changes, causing PA hypertension and retroperitoneal fibrosis
b. Ergotamine—causes fibrotic valve lesions
2. Appetite suppressants: fenfluramine and dexfenfluramine
a. These drugs cause valve regurgitation involving both right- and left-sided valves. Histopathology showed the characteristic plaques of myofibroblasts with excessive extracellular matrix.
b. Meta-analysis of nine case-control studies showed evidence that regurgitation was due to the drug, not obesity, and that AR was more common than mitral regurgitation (MR).
c. Aortic insufficiency (AI) occurred more often if drug was taken >3 to 6 months. Pulmonary hypertension could result from short-term treatment. Furthermore, regurgitation may decrease or stabilize when drug is discontinued.
3. Benfluorex. Used for overweight diabetics or for hypertriglyceridemia. Several case reports found unexplained MR. Later, a multicenter registry showed consistent presentation of middle-aged obese women with or without diabetes treated with benfluorex presenting with MR and congestive heart failure (CHF). Leaflet thickening and retraction with involvement of the subvalvular apparatus were found. Stenosis was uncommonly seen, and multivalvular involvement was often present. One study in diabetics showed that regurgitant lesions were more common in patients treated with benfluorex compared with controls (odds ratio 2 to 3:1 depending on which valve was involved).
4. Ergot-derived Dopaminergic Agonists
a. Pergolide used for Parkinson disease (improves bradykinesia and rigidity)
b. Cabergoline used for Parkinson disease or hyperprolactinemic disorders
c. When these drugs were used to treat Parkinson disease, there was a significant increase in the incidence of valvular disease compared with patients treated with other (non-ergot-derived) dopamine agonists, with a sevenfold increase in regurgitant lesions with pergolide and a fivefold increase with cabergoline.
i. With pergolide, valvular heart disease is generally plurivalvular although mitral valve involvement was greater than aortic or tricuspid. The agent was withdrawn in the United States, whereas use in Europe was limited to patients with Parkinson disease resistant to other dopaminergic agonists and with very careful echocardiographic follow-up.
ii. Cabergoline used for treating hyperprolactinemic patients (first-line agent for this indication) restores normal prolactin levels and gonadal function at low doses. At low dose, the risk of valvular regurgitation is unconfirmed.
5. MDMA (Ecstasy)
There are reports of significant valvular regurgitation with long-term use (3 to 6 tablets/wk for 6 years) with the severity of regurgitation correlated to the dose.
D. Future research to evaluate drug safety
An animal model of drug-induced valvular heart disease has been developed (with Wistar rats). These animals developed valvular pathology with similar echocardiographic features and histopathology when exposed to pergolide. Use of a 5-HT2B antagonist blocked the development of these valvular lesions when the rats were exposed to pergolide. New drugs should be analyzed for 5-HT2B agonist activity to predict possible valvulopathy before large clinical trials.
II. PREGNANCY AND VALVULAR HEART DISEASE
Pregnancy in patients with valvular heart disease can cause maternal and offspring morbidity and mortality. Cardiovascular disease is responsible for 10% to 15% of maternal mortality. The valvular disease can be acquired or congenital. The most common causes in pregnant patients include congenital (Marfan syndrome) and acquired (rheumatic) valvular disease.
The relative rates at which these etiologies are encountered depend on whether the woman is from a lower- to middle-income nation (rheumatic heart disease predominates) or a higher-income nation (congenital heart disease predominates). While rheumatic
heart disease is declining in the developed world, overall it accounts for 90% of heart disease in women of child-bearing age in nonindustrialized nations. To minimize the morbidity and mortality in these patients with valvular disease, a preconception evaluation is recommended.
heart disease is declining in the developed world, overall it accounts for 90% of heart disease in women of child-bearing age in nonindustrialized nations. To minimize the morbidity and mortality in these patients with valvular disease, a preconception evaluation is recommended.
A. Risk assessment tools for patients with valvular heart disease
1. CARPEG (Cardiac Disease in Pregnancy): Four predictors of maternal cardiac events during pregnancy:
a. Prior cardiac event or arrhythmia
b. New York Heart Association (NYHA) functional class >2 or cyanosis
c. Left heart obstruction
d. Systemic ventricular dysfunction
2. ZAHARA (translates to Pregnancy in Women with Congenital Heart Disease):
Eight predictors of risk:
a. History of arrhythmic event
b. Baseline NYHA functional class >2
c. Left heart obstruction (peak aortic valve gradient >50 mm Hg)
d. Mechanical valve prosthesis
e. Moderate/severe systemic atrioventricular valve regurgitation (possibly from ventricular dysfunction)
f. Use of cardiac medication prepregnancy
g. Repaired or unrepaired cyanotic heart disease
h. Severe pulmonary arterioventricular valve regurgitation
3. Modified World Health Organization (WHO) classification: There are a variety of models that predict risk; however, the modified WHO classification appears to be the most useful. See Tables 10.2 and 10.3 illustrating the WHO risk principles and WHO risk by cardiac disease.
B. Elements of preconception assessment and counseling
1. Careful history, family history, physical exam (including screening for connective tissue disorders)
2. 12-lead electrocardiogram (ECG)
TABLE 10.2 Modified WHO Classification of Maternal Cardiovascular Risk: Principles | ||||||||||||
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TABLE 10.3 Modified WHO Maternal Cardiovascular Risk Classification by Cardiac Diagnosis | ||||||||||||||
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3. Transthoracic echocardiogram—valve assessment and aortic size
4. In certain patients, functional capacity and symptoms should be assessed using stress testing. Prepregnancy symptoms often predict adverse outcomes during pregnancy or labor and delivery. One study found that women who achieve prepregnancy heart rate (HR) ≥150 bpm and/or peak oxygen uptake >25 mL/mg/min may be considered to have safer or better pregnancy outcomes.
5. Counseling on the basis of risk assessment to discuss maternal and fetal risks for complications and mortality. Discuss risks of therapy, including risk of miscarriage, early delivery, growth retardation resulting in small for gestational age infant, and possible fetal congenital defects. On the basis of risk, a discussion regarding contraception method should be included. These discussions are best approached by a multidisciplinary group including an obstetrician/gynecologist and a cardiologist.
Women considered at high risk owing to valvular lesions should be considered for definitive treatment of the lesion before pregnancy. If valve surgery is needed, repair is preferable to replacement, and if replacement is needed, a careful discussion should occur regarding choice of prosthesis. Although a bioprosthesis is preferable because it does not require anticoagulation, it is not as durable as a mechanical prosthesis and will require reoperation sooner owing to degeneration. A bioprosthesis would allow a patient to go through her pregnancy without the risks of anticoagulation (bleeding risks, valve thrombosis, or even fetal teratogenesis in the first trimester).
C. Patients at prohibitively high risk are those in WHO classification IV, who should be counseled against pregnancy. These include:
1. Severe symptomatic aortic stenosis (AS) or mitral stenosis (MS)
2. Cardiomyopathy with left ventricular ejection fraction (LVEF) ≤30%
3. Marfan syndrome with aortic root ≥45 mm
4. Advanced pulmonary hypertension (two-thirds systemic pressures)
5. Eisenmenger syndrome
6. History of peripartum cardiomyopathy with LVEF not fully recovered
D. Cardiac considerations for contraception
1. Contraceptive options include combined hormonal contraceptives, progestin-only contraceptives, intrauterine devices (IUDs), barrier methods, and sterilization/permanent forms of contraception.
2. Specific issues include the increased risk of thromboembolic events and hypertension with estrogens. Thus, combined hormonal contraceptives (pills, patches, or vaginal rings) are not recommended for the following:
a. Mechanical prostheses because of risk of valve thrombosis
b. Eisenmenger syndrome because of risk of pulmonary embolism
c. Intracardiac shunts because of risk of paradoxical embolus
3. Monthly injections with medroxyprogesterone are contraindicated in patients with CHF owing to risk of fluid retention. Barrier methods and IUDs releasing levonorgestrel are safest in patients with cardiomyopathy with decreased left ventricular (LV) function, pulmonary hypertension, and cyanotic heart disease. Patients with prohibitively high-risk pathology may wish to consider permanent forms of contraception.
4. In general, stenotic lesions are poorly tolerated, whereas regurgitant lesions are better tolerated. Although individual lesions will be discussed, including management, in further detail to understand the pathophysiology that occurs with valvular disease in pregnancy, one must first consider the normal physiologic/hemodynamic changes that occur with pregnancy.
E. Physiologic and hemodynamic changes in pregnancy
1. Cardiac output increases 30% to 50% (increased HR and stroke volume).
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