Calcification of the Aortic Valve in the Dialyzed Patient (2000)

Cardiovascular disease is the leading cause of mortality in patients with end-stage renal disease (ESRD), with cardiac disease alone accounting for 40% of all deaths. Ischemic heart disease, heart failure, and cardiomyopathy are the most frequent causes of cardiac death (1), but valvular abnormalities are also common in these patients and may cause significant morbidity and mortality (2,3,4,5,6,7,8,9). In principle, the origin of valvular alterations can be congenital, infectious, or dystrophic (10). The majority of valvular lesions observed in ESRD patients are acquired, mostly secondary to dystrophic calcification of the valvular annulus and the leaflets. The mitral and aortic valves are the preferential sites for dystrophic valvular calcification in ESRD. For a long time, the calcification of the aortic valve and annulus was considered an age-associated degenerative lesion with little functional importance. Recent studies of elderly subjects in the general population have shown, however, that aortic-valve sclerosis carries an increased risk of death from cardiovascular disease and myocardial infarction (11). In ESRD patients, aortic-valve sclerosis and calcification may progress rapidly and calcific aortic stenosis (AS) develops frequently (7,9,12). With the age of patients treated by dialysis increasing constantly, the prevalence of aortic valve calcification and its complications will increase in parallel. Epidemiology Prevalence and Incidence In the general population, sclerosis, thickening, or calcification of the aortic valves in the absence of left ventricular (LV) outflow obstruction is observed principally in the elderly. It affects 20 to 30% of the population over 65 yr of age, and functionally relevant AS is present in about 2% (11,13,14). The prevalence of aortic sclerosis and AS increases with age and is found in 48 to 53% and 4 to 5%, respectively, of adults over 85 yr of age (11). In ESRD patients, the prevalence of aortic valve calcifications is also 28 to 55%, but it occurs 10 to 20 yr earlier than in the general population (2,6,7,9). ESRD patients with aortic valve calcification are older than those with noncalcified valves. As in the general population, the prevalence of hemodynamically asymptomatic aortic valve calcification increases with age. Hemodynamically significant AS is found in 3 to 9% of patients (2,9,15), and the incidence of symptomatic AS is 3.3% per year in hemodialyzed patients (9). In a large multicenter survey of 230 chronic dialysis centers in France (7), the annual incidence of severe valvular heart disease (mitral and aortic combined) was 15 to 19 cases per 10,000 dialyzed patients. Valve calcification in the absence of known preexisting valvular disease accounted for 69% of all cases of severe valvulopathy. Of the patients with calcific valvular disease, 51% had AS. Etiology and Pathophysiology Acquired calcification and/or stenosis in ESRD is usually infectious or degenerative in origin (7). In the early stages, the anatomy of these two conditions is rather specific, but the specificity is lost when progressive calcification supervenes. Valvular disease of infectious origin has decreased in frequency, and today the majority of calcific aortic valve disease in the general population is degenerative (senile) in origin. In degenerative aortic calcification, the lesions are first seen at the site of valve insertion. They extend in the direction of the cusps. Commisural fusion is present only in advanced stages when calcium deposits protrude and fuse the valve leaflets (10). Aortic calcification in ESRD patients is almost constantly associated with widespread calcification of the myocardium, mitral valves, aorta, and large- or medium-sized arteries, including coronary arteries (6). The degenerative (wear and tear) etiology appears to underlie the dystrophic calcification of aortic valves (10). Aortic valves are submitted to cyclic mechanical stress. The stress is related to pressure gradients and turbulent blood flow resulting from the high acceleration rate and peak velocity when blood flows through the aortic valve. Apart from cyclic opening and closure of the valves, high frequency vibration of the leaflets is produced by turbulent flow. Over the lifespan, the repetitive mechanical stress causes fatigue and rearrangement of bioelastomers, leading to microfractures in the biomaterials ultimately resulting in fibrosis and calcification. Calcification further increases peak ejection velocity and causes turbulent blood flow, thus creating a vicious cycle. Renal failure and dialysis superimpose futher pathomechanisms. This conclusion is supported by the observation that a correlation is found between duration of hemodialysis treatment and presence of heart valve calcification (4,5) (Table 1).Table 1: Logistic regressionaESRD promotes valvular disease by hemodynamic and biochemical mechanisms. The blood flow velocity and the degree of turbulence across the aortic valve are determined by aortic valve area and blood flow rate (stroke volume). As a result of anemia, arteriovenous (AV) shunts, and overhydration, cardiac output is increased in patients on hemodialysis. Even in patients with normal valve area, these conditions can increase peak flow velocity and generate flow turbulence. Moreover, the heart rate is increased. This causes an increased number of opening/closure cycles and a higher rate of repetitive stress. The role of systemic hypertension in the pathogenesis of aortic-valve calcification is uncertain, although a significant correlation was found in some (8) but not all studies (9,16). The number of years on hemodialysis treatment is significantly correlated with the presence of aortic calcification. This observation is presumably explained by the progressively longer time during which the patients are exposed to the above hemodynamic and biochemical risk factors. As mentioned above, calcification of the aortic valves is usually associated with extensive atherosclerosis involving the coronary arteries and the major central elastic arteries, for instance, the aorta. The two pathologies presumably share common atherogenic factors in their pathogenesis (6). In the general population, both diabetes mellitus and hypercholesterolemia are risk factors for development of the valvular lesion (10,17). According to recent studies, atherogenesis and presumably also degenerative disease of the aortic valves involve accumulation of lipids; oxidized LDL in particular is associated with a chronic inflammatory process with accumulation of macrophages and T lymphocytes and culminates in calcium deposits (18,19,20). A similar chronic proinflammatory state and increased concentrations of oxidized LDL are also observed in hemodialyzed patients. Dystrophic calcifications are most consistently associated with disorders of phosphorus and calcium metabolism, particularly an elevated calcium-phosphorus product (Ca × P) (2,4,6,9). Poor phosphorus control and hyperphosphatemia are the principal culprits (8,9) (Table 1), while hypercalcemia and parathyroid hormone excess play an ancillary role (4,5,6). Undoubtedly, in ESRD patients secondary hyperparathyroidism can cause hyperphosphatemia, hypercalcemia, and high a Ca × P product, conditions favorable for the development and progression of calcification. Nevertheless, valvular calcification may occur in ESRD patients even in the absence of secondary hyperparathyroidism. Indeed, in the study of Ureña et al. (9), in 62% of the patients with AS it was shown that hyperphosphatemia was associated with signs of adynamic bone disease and not with hyperparathyroidism. In the general population, the presence of dystrophic calcifications of the cardiovascular system are correlated with low bone mass and the presence of osteoporosis (21). In ESRD patients, adynamic bone disease is associated with an increased frequency of hyperphosphatemia, hypercalcemic episodes, and extraskeletal calcifications. In the study of Braun et al. (6) on dialyzed patients, the presence of calcifications of the aortic valves was associated with a higher frequency and severity of coronary calcifications. The coronary calcium score was inversely related to bone mass. Increasing use of calcitriol and calcium-containing phosphate binders increases the enteral calcium absorption and may favor the development of hypercalcemia, increased Ca × P product, adynamic bone disease, and secondary hyperphosphatemia. All of these conditions also favor the development of valvular calcifications. In the study by Ureña et al. (9), plasma 25(OH) vitamin D3 concentrations were higher in dialysis patients with AS. The functional and structural consequences of aortic valve calcification depend on the degree of LV outflow obstruction. When aortic valve calcification progresses so that hemodynamically significant obstruction occurs, the LV is submitted to an increasing pressure load and develops compensatory hypertrophy (10). Elevated systolic wall stress from LV pressure overload promotes an adaptive process, characterized by parallel addition of sarcomeres resulting in a disproportionate increase of LV wall thickness in the presence of a normal chamber radius, i.e., concentric hypertrophy (22). LV hypertrophy is both beneficial and detrimental. The benefit is linked to the fact that the number of sarcomeres, the wall thickness, and the working capacity of the LV are increased while at the same time parietal tensile stress is kept stable, so that energy is spared. These beneficial effects permit maintenance of normal systolic function during the phase of compensated adaptive hypertrophy. Nevertheless, even during this phase of compensated hypertrophy, LV relaxation and diastolic filling are already impaired (10). In patients with severe AS, LV diastolic pressure is elevated. A further increase occurs during atrial systole, secondary to enhanced contraction of the hypertrophied left atrium. Atrial contraction plays an important role in filling the noncompliant left ventricle. Loss of an appropriately timed atrial contraction as occurs in atrial fibrillation may result in dramatic clinical deterioration in patients with AS (10). While the beneficial effects of LV hypertrophy dominate in the initial phase of adaptation to overload, later in the course of the disease sustained overload leads to the development of cardiomyopathy, so-called “cardiomyopathy of overload.” This phase is characterized by the depression of the contractile state and dilation of the LV with abnormal elevation of systolic wall stress, decline in ejection fraction, and reduction of cardiac output. In this maladaptive phase, the oxygen consumption and energy expenditure of the overloaded myocardial cells are increased, leading to a chronic energy deficit. When oxygen consumption is increased, the LV ejection time is prolonged, the diastolic time is shortened, and wall stress is increased (23). The pathogenesis of the chronic energy deficit is complex and involves an impairment of coronary circulation and decreased coronary reserve. In the genesis of the coronary malfunction, several factors play a role: (1) medial hypertrophy of small coronary vessels with raised coronary resistance and reduced maximal dilation; (2) increased resistance to coronary flow caused by higher extravascular compressive forces exerted by the hypertrophic myocardium; (3) upward shift of the plateau of autoregulated coronary flow (absolute coronary flow is increased but flow per gram of tissue is decreased); (4) shift of the autoregulatory range to higher perfusion pressures; (5) diminished relative myocardial capillary density; and (6) decrease in the duration of the diastole due to increased LV ejection time. Because in the subendocardium the resistance to flow is higher and the metabolic demand is greater, the subendocardial layers are more susceptible to ischemia than the subepicardial layers. The increase in extracellular matrix and collagen content permits the maintenance of the mechanical efficiency of the contracting heart at the expense of impaired diastolic filling. Another factor that accounts for abnormal diastolic function of hypertrophied myocardium are lusitropic abnormalities, i.e., delayed relaxation as a result of the slower reuptake of calcium by the sarcoplasmic reticulum. The prolongation of cytosolic calcium transients increases the duration of the action potential. Delayed afterdepolarization contributes to arrhythmias, which are further favored by conduction abnormalities linked to the fibrosis and enlargement of hypertrophied hearts (23). In patients with ESRD and LV outflow obstruction, the pressure overload is accompanied by flow/volume overload caused by anemia, AV shunts, and sodium and water retention. In some cases, aortic regurgitation resulting from dystrophic calcification further augments flow/volume overload of the LV (24). Superposition of flow to pressure overload in ESRD accelerates the development of LV enlargement and LV hypertrophy (25). Clinical Manifestations Natural History The natural history of nonstenotic aortic valve calcification in ESRD patients has not been systematically analyzed in longitudinal studies. In nonuremic patients, aortic valve sclerosis is associated with a 50% increase in the risk of death from cardiovascular causes, and this is true even in the absence of hemodynamically significant obstruction of the LV outflow (11). Simple calcifications are clinically asymptomatic, but are frequently associated with: restricted motion of the leaflets, hindered aortic valve opening, and decreased area of the valvular orifice. The aortic valve area is highly dependent on body surface area and age. The effect of age on aortic valve opening and orifice is particularly pronounced in ESRD patients (Figure 1). The natural history of aortic calcification in ESRD patients is frequently characterized by rapid evolution from the stage of asymptomatic calcification to the stage of severe valvular stenosis (2,7,9). In a study of Ureña et al. (9), the mean time interval was 16.8 ± 1.9 mo. The mean annual decrease in aortic valve area in those patients who developed AS was 0.23 cm2/yr (0.3 cm2/m2) compared with 0.05 to 0.1 cm2/yr in nonuremic patients. Progression toward AS was significantly more frequent in men. Such rapid progression of AS was associated with a significant decrease in survival. In the study of Ureña et al. (9), mean survival after the onset of symptomatic AS was 23 ± 9.4 mo. In the study of Baglin et al. (7), patients who underwent surgery for calcific valvulopathy and AS had a median survival of 36 mo. Among patients who did not undergo surgery, median survival was 13 mo.Figure 1.: Correlation between age and aortic valve area in the general population (left panel) and end-stage renal disease (ESRD) patients (right panel). The figure illustrates a more pronounced age dependency of valve area in ESRD patients.In ESRD patients, the signs and symptoms of AS are similar to those in nonuremic patients, i.e., angina pectoris, syncope, and heart failure (10). The most common causes of death are heart failure and sudden death. Even in patients without coronary artery disease, angina may occur because of the combination of increased oxygen demand and reduction of oxygen supply. But in ESRD patients, generalized atherosclerosis also involving coronary arteries is frequently associated with aortic calcification and stenosis and must be excluded in all patients with AS who develop angina. Syncope may occur in ESRD patients with AS as a consequence of exertional vasodilation or a vasodepressor response. Syncope at rest may be induced by atrial fibrillation, which is the most frequent dialysis-induced arrhythmia. Loss of synchronized atrial contraction leads to a precipitous decline of cardiac output. Heart failure is common in ESRD patients with AS and it is usually precipitated by volume overload. Diagnosis Physical Examination Auscultation reveals the typical ejection murmur, which is maximally audible at the level of the right third intercostal space, is usually diamond-shaped with maximal intensity during meso-systole, is reinforced after a long diastole interval (for instance, after a premature beat), and is transmitted to the carotid area. Nevertheless, heart murmurs are frequently noted in ESRD patients without valvular abnormalities, probably as the result of a hyperkinetic circulation with flow and pressure overload from AV fistula, anemia, and hypertension. Laboratory Examination The electrocardiogram shows the signs of pressure overload, i.e., an abnormally high Sokolow-Lyons index associated with repolarization abnormalities in the left side precordial leads. The x-ray is of limited diagnostic value. It may show aortic valve calcification and a high cardiothoracic index. Doppler echocardiography is the best tool for diagnosis and follow-up. One can easily calculate the transaortic pressure gradient (in mmHg), based on the simplified Bernoulli's law, and the valve area, based on the continuity equation. One assumes that for a given flow within a tube, the product of aortic-valve section area (AVa) and aortic velocity (AoV) is equal to the product of LV outflow area (LVOa) and LV outflow velocity (LVOV) according to the formula: AVa × AoV = LVOa × LVOV. Assuming a circular section area, LVOa is quantified by measurement of the diameter of the outflow tract using bidimensional echocardiography. 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