Pathophysiology of cardiovascular disease in hemodialysis patients

Kidney International, Vol. 58, Suppl. 76 (2000), pp. S-140–S-147

Pathophysiology of cardiovascular disease in hemodialysis patients FRE´DE´RIQUE MEEUS, OLIVIER KOURILSKY, ALAIN P. GUERIN, CATHERINE GAUDRY, SYLVAIN J. MARCHAIS, and GE´RARD M. LONDON Center Hospitalier Louise Michel, Evry, and Center Hospitalier F.H. Manhes, Fleury-Me´rogis, France

Pathophysiology of cardiovascular disease in hemodialysis patients. Cardiovascular disease is the principal cause of morbidity and mortality in dialysis patients. The principal alterations responsible are left ventricular hypertrophy and arterial disease characterized by an enlargement and hypertrophy of arteries and the high prevalence of atheromatous plaques. Left ventricular hypertrophy is the consequence of combined effects of chronic hemodynamic overload and nonhemodynamic biochemical and neurohumoral factors characteristic of uremia. The hemodynamic overload is due to flow and pressure overload. The flow overload is tightly related to hyperkinetic circulation caused by anemia, arteriovenous fistula, or overhydration and is characterized by an enlargement of the left ventricular cavity. The pressure overload in these patients is more tightly related to abnormal geometry and function of large conduit arteries, principally the stiffening of arterial tree. The flow overload is also in large part responsible for remodeling of arterial tree, and as the heart and vessels are a coupled interactive physiological system, cardiac and vascular alterations occur in parallel, being induced to a great extent by the same hemodynamic abnormalities. The principal clinical consequences of left ventricular hypertrophy and arterial alterations are heart failure, ischemic heart disease, and peripheral artery disease. Cardiovascular alterations are only partly reversible, and efforts should be directed toward early prevention.

Cardiovascular disease is the leading cause of mortality among patients with end-stage renal disease (ESRD), with cardiac disease alone accounting for 40% of deaths [1, 2]. Cardiomyopathy and ischemic heart disease are the most frequent causes of cardiac death [3–5]. At all ages, dialysis patients are at a 10- to 20-fold increased risk of death from a cardiovascular cause, with the relative risk being higher in younger patients and declining with age [2]. Left ventricular hypertrophy (LVH) is the most frequent cardiac alteration in ESRD and is an independent risk factor for survival in these patients [6–9]. Epidemiological and clinical studies have shown that damage of large arteries is a major contributory factor Key words: heart failure, intensive care, dialysis mortality, arterial disease, left ventricular hypertrophy.

 2000 by the International Society of Nephrology

to the high mortality of ESRD patients. Macrovascular disease develops rapidly in uremic patients and is responsible for the high incidence of ischemic heart disease [1, 2]. Although the majority of these accidents may be due to atherosclerotic obstructive lesions, in 25 to 30% of these patients its origin is nonatherosclerotic, being associated with microvascular disease or fibroelastic thickening of the aorta and reduced arterial compliance [3, 10, 11] associated with nonatherosclerotic arterial remodeling [11–14]. The cardiac and vascular abnormalities share several common pathophysiological mechanisms and are frequently interrelated [11]. The purpose of the present article is to summarize the pathophysiological mechanisms of cardiac and arterial alterations in ESRD patients undergoing replacement therapy. PATHOPHYSIOLOGY OF CARDIAC HYPERTROPHY Left ventricular hypertrophy is an adaptive response to increased cardiac work (Fig. 1). The initiating signal includes myocardial stretch increasing the LV tensile stress [15, 16]. Increased cardiac work is frequently associated with increased release of neurotransmitters and vasoactive substances that may have a permissive or direct effect on cardiomyocyte growth [17, 18]. LVH is both beneficial and detrimental. The benefit is linked to an increased number of sarcomeres, enhancing the working capacity while keeping the parietal tensile stress stable, thus sparing energy [17, 18]. This beneficial effect maintains normal systolic function during the initial phase of compensated “adaptive” LVH. The sustained overload leads progressively to “maladaptive” hypertrophic response [16]. In the maladaptive phase of LVH, the active myocardial cells have an imbalance between energy expenditure and production, resulting in a chronic energy deficit and accelerated death of myocytes [15, 16]. The increase in extracellular matrix and collagen content permits maintenance of the mechanical efficiency of the contracting heart at the expense of impaired diastolic

S-140

Meeus et al: Cardiovascular disease in dialysis patients

Fig. 1. Correlation observed in ESRD patients between stroke work index and left ventricular mass index (r ⫽ 0.62; P ⬍ 0.0001).

filling. LVH usually develops in a pattern specific to the initiating mechanical stress [15, 16]. Pressure overload results in a parallel addition of new sarcomeres with a disproportionate increase of the LV wall thickness and normal chamber radius (concentric hypertrophy). Volume overload results primarily in the addition of new sarcomeres in series and secondarily in the addition of sarcomeres in parallel, resulting in an enlargement of the LV chamber with an increased wall thickness sufficient to counterbalance the increased radius (eccentric hypertrophy) [15]. The development and characteristics of LVH are influenced by several other factors, such as age, gender, race, and coexistent diseases like diabetes, systemic diseases, or renal failure. CARDIAC HYPERTROPHY IN DIALYSIS PATIENTS The prevalence of LVH is high among ESRD patients. The structural alterations occur early in the course of renal failure. In a prospective study in patients starting renal replacement therapy, 74% of the patients had LVH, and high LV mass index was an independent predictor of death after two years of treatment [19]. In dialysis patients, as many as 80% of patients have an increased LV mass [6–19]. The increase in the LV mass in ESRD patients can be due to an increase in either LV enddiastolic diameter or LV wall thickness and combines the features of both eccentric and concentric hypertrophy [4, 6, 8]. The precise classification of LVH as an eccentric or concentric type is sometimes difficult in hemodialysis patients because of cyclic variations in extracellular fluid volume and humoral balance. The internal dimensions of the LV are influenced by volume status, and the contraction of blood volume during the dialysis session decreases the LV diameter, thus inducing “acute” changes

S-141

in the relative wall thickness of the LV [6]. In stable patients with compensated hypertrophy, the systolic function remains in the normal range, while the diastolic filling is frequently altered [6–8]. Left ventricular hypertrophy in ESRD patients is principally due to an increase in LV minute work resulting from volume and pressure overload [8, 20]. Nevertheless, experimental and clinical studies demonstrated that the cardiovascular structural changes in ESRD are in part independent from hemodynamic factors [21–25]. In experimental renal failure, increased cardiac mass with interstitial fibrosis [26], reduced capillary density, and increased intramyocardial arteriolar wall thickness has been demonstrated [27, 28]. Experimental studies have shown that parathyroid hormone could have a permissive role in the cardiac fibrogenesis and the activation of cardiac fibroblasts [21]. Cardiac remodeling in experimental uremia is characterized by activation of postmitotic cardiomyocytes [22], possibly predisposing to apoptosis and “maladaptive” hypertrophy [29]. The LV of ESRD patients is characterized by an expansion of the cardiac interstitium. The latter is more prominent than in patients with diabetes or primary essential hypertension with comparable LV mass [26]. Intramyocardial fibrosis in hemodialyzed patients with secondary hyperparathyroidism could account for the development of an inadequate hypertrophy with persistence of high LV systolic stress [30]. Nevertheless, the role of hyperparathyroidism is controversial, and parathyroidectomy did not produce significant effects on cardiac structure and function [31–33]. With some exception [24], an association of LVH and plasma renin-angiotensin activity was not demonstrated [23]. Nevertheless, angiotensin I-converting enzyme (ACE) inhibitors are able to partially regress LVH independently of their antihypertensive effect, suggesting that the tissular and cardiac renin-angiotensin system could play a role in the pathogenesis of LVH in uremic patients [23]. A recent study by Demuth et al showed that the increased plasma endothelin in ESRD patients was associated with LVH, suggesting that endothelin may be of pathophysiological significance in the process of cardiac remodeling [25]. The influence of endothelin in the cardiac remodeling was also demonstrated experimentally in rats in which the endothelin receptor antagonists were able to attenuate the development of myocardial hypertrophy [34]. Low serum albumin in ESRD was associated with the development of heart failure in progressive dilation of the LV [4, 7]. The causal mechanisms of this association are not clear. Hypoalbuminemia could reflect the existence of an inflammatory state characterized by increased C-reactive protein, fibrinogen, and cytokines, which are considered as cardiovascular risk factors. In ESRD patients, hypoalbuminemia is also associated with the presence of atheromatous plaques [35] and abnormal endothelial function

S-142

Meeus et al: Cardiovascular disease in dialysis patients

changes and LV mass, as well as stroke volume [6, 8, 20]. A progressive and frank LV dilation is observed in the maladaptive phase of LVH, whatever its origin (anemia, hypertension, hypoalbuminemia, ischemic heart disease). In these conditions, the LV systolic function is depressed with clinical signs of cardiac failure and/or ischemic heart disease [4]. Pressure overload

Fig. 2. Correlation between hematocrit and stroke volume index in dialysis patients (r ⫽ 0.27; P ⬍ 0.005).

[36]. Hypoalbuminemia may affect endothelial function and may inhibit nitric oxide (NO)-mediated vascular relaxation and LV/vascular coupling [37, 38]. HEMODYNAMIC FACTORS AND CARDIAC HYPERTROPHY IN ESRD PATIENTS Three factors are involved: (1) an increased stroke volume and hyperkinetic high-output state (flow/volume overload), (2) an increased opposition to LV ejection (pressure overload), and (3) an increased heart rate [5–8]. Volume/flow overload Volume/flow overload is characterized by an increased stroke volume and cardiac output in association with an increase in the LV end-diastolic diameter [4, 6, 8, 20]. The LV enlargement in ESRD patients is attributable to: (1) anemia (Fig. 2), (2) arteriovenous (AV) shunts, and (3) sodium and water retention [7, 8, 39]. In a recent prospective study by Levin et al, a decline in the hemoglobin level was an independent predictor of LV growth in early renal disease [40]. In patients on dialysis therapy, the correction of anemia with epoetin decreases the hyperdynamic circulatory state and induces partial regression of LVH, principally by reducing the internal dimensions of the LV [41–43]. Cardiomegaly with high-output cardiac insufficiency occurs as a complication of highflow AV shunts. The creation of an AV shunt for hemodialysis access is in part responsible for LV dilation and a high-output state [6, 8]. However, symptomatic cardiac failure caused by AV shunts alone is uncommon and occurs more frequently in patients with underlying cardiac disease. The internal dimensions of the LV, the stroke volume, and the end-diastolic pressure are directly related to the circulating blood volume, and there is a direct correlation between interdialytic body weight

In ESRD patients, the correlation between LV mass and blood pressure (BP) is weak, and experimental and clinical studies have shown that LVH develops even in normotensive conditions [6, 8, 23, 44]. Since BP is the easiest measurable index of opposition to LV ejection, afterload is usually taken to be a function of the pressure against which the LV must eject. BP is an integrated nonspecific external load on the LV affected by complex interactions between the properties of the arterial system and the characteristics of LV ejection [45]. The ill effects of hypertension are usually attributed to a reduction in the caliber or the number of arterioles, resulting in an increase in peripheral resistances. Peripheral resistances are a determinant (with cardiac output) of mean arterial pressure, in which the pressure and flow are considered as constant over time. This definition does not take into account the fact that BP is a cyclic oscillating phenomenon with systolic and diastolic BP being merely the limits of these oscillations, and that in the arterial system the mean BP is a virtual pressure. Moreover, systolic BP is amplified from the aorta to the peripheral arteries, and brachial artery systolic BP only indirectly reflects the systolic BP in the aorta and LV [45]. The appropriate term to define the arterial factor(s) opposing LV ejection is aortic input impedance, which depends on: (1) peripheral resistance, (2) the viscoelastic properties of the aorta and central arteries, and (3) the inertial forces represented by the mass of the blood in the aorta and LV [45]. Peripheral resistance as a determinant of mean BP sets the general level at which the pressure wave will fluctuate. The amplitude of the fluctuation (pulse pressure) is influenced by the viscoelastic properties of the aorta and large arteries and by the characteristics of LV ejection (stroke volume and ejection velocity). These viscoelastic properties can be described in terms of compliance, distensibility, or stiffness [45, 46]. Stiffening of arterial walls (decreased compliance and distensibility) can increase the LV afterload independent of peripheral resistances. This situation is clinically characterized by a large amplitude of the arterial pressure wave (pulse pressure) caused by high systolic and/or low diastolic pressure or both [45]. Two mechanisms are involved. The first involves generation of high systolic pressure by the LV ejecting into a stiff arterial system, and a decreased diastolic recoil resulting in lower diastolic pressure. The second acts through the influence of arterial

Meeus et al: Cardiovascular disease in dialysis patients Table 1. Cardiac parameters in control subjects and end-stage renal disease patients (ESRD) Parameters LV-EdiD mm LV-EsyD mm PWTh mm IVSTh mm LV mass index g/m2 % shortening E/A ratio Stroke index mL/m2 Cardiac index mL/min/m2 Total peripheral resistances dyne · s · cm5 · m2

Controls N ⫽ 82

ESRD N ⫽ 110

51.0 ⫾ 4.5 31.5 ⫾ 4.5 9.3 ⫾ 1.5 9.4 ⫾ 2.0 109 ⫾ 28 38.0 ⫾ 5.2 1.25 ⫾ 0.36 44.0 ⫾ 6.7 3008 ⫾ 772

53.5 ⫾ 5.5a 35.0 ⫾ 6.0a 10.5 ⫾ 2.0a 11.0 ⫾ 2.0a 163 ⫾ 51a 35.0 ⫾ 6.3a 0.98 ⫾ 0.36a 52.0 ⫾ 12.0a 3516 ⫾ 850a

2972 ⫾ 760

2522 ⫾ 695a

Values are means ⫾ standard deviation. a P ⬍ 0.001 Abbreviations are: LV-EdiD, left ventricular end-diastolic diameter; LV-EsyD CCA, left ventricular end-systolic diameter; PWTh ⌬P, posterior wall thickness; IVSTh, interventricular septal thickness.

stiffness on pulse wave velocity (PWV). Arterial stiffening accelerates PWV and the propagation of pressure waves along the arterial tree. The pressure wave generated in the aorta reaches the peripheral reflecting sites earlier and generate a reflected wave, which returns earlier to the aorta, amplifying aortic and ventricular pressures during systole and reducing aortic pressure during diastole [45, 46]. The principal consequences of these changes are the development of LVH and alterations of coronary perfusion pressure [45–49]. Total peripheral resistance is usually not increased in patients undergoing dialysis (Table 1), and the principal factors of pressure overload are represented by changes in the viscoelastic properties and geometric properties of the arterial system. ARTERIAL CHANGES IN DIALYSIS PATIENTS The remodeling of arterial system in ESRD as well as in the general population is heterogeneous. Atherosclerosis (development of plaques) and remodeling are associated with aging (arteriosclerosis) and hemodynamic alterations [11–14, 35]. Atherosclerosis and arterial occlusive lesions are the most frequent causes of cardiovascular morbidity in patients on renal replacement therapy [1, 2]. Occlusive lesions principally involve the medium-sized conduit arteries, and coronary insufficiency, peripheral artery disease, and cerebrovascular events occupy an important place in the mortality of these patients. The high incidence of atherosclerosis-related complications led Lindner et al to hypothesize that atherogenesis is accelerated in chronic hemodialysis patients [50]. However, whether the atherogenesis of dialysis patients is accelerated and whether the nature of atherosclerotic plaques is similar in hemodialysis patients and the general population remain matters of debate. Ultrasonographic studies have shown

S-143

a much higher prevalence of calcified plaques in ESRD patients than in age-matched controls in whom soft plaques are more frequent [35]. While ESRD produces atherogenic factors essentially unique to uremia, including dyslipidemia, calcium-phosphate alterations, malnutrition, and activation of cytokines, these factors are additive to the number of risk factors observed in subjects with preserved renal function, such as age, hypertension, smoking, diabetes, male gender, and insulin resistance. Many hemodialysis patients already have significant vascular lesions before initiating dialysis, and in many patients, especially older patients, the generalized atherosclerosis can be the primary cause of renal failure. Hypertension is a frequent complication in ESRD, and an association between high BP and occlusive arterial lesions was found in chronic hemodialysis patients. Rigorous control of hypertension at the time of incipient renal failure led to a significant decrease in the incidence of myocardial ischemia after initiation of dialysis therapy [51]. Besides atherosclerosis and the presence of plaques, the arterial system of ESRD patients undergoes remodeling that is characterized by dilation and to a lesser degree, arterial intima-media hypertrophy of central, elastic-type, capacitative arteries such as the aorta or the common carotid artery [11–14, 35]. Arterial remodeling is less pronounced in peripheral, muscular-type, conduit arteries, such as the radial artery [52]. In ESRD patients, this remodeling is associated with arterial stiffening [11] caused principally by an increase in the Einc (incremental elastic modulus), which characterizes the intrinsic properties of wall material. The effect of increased Einc is, in part, attenuated by the increase in arterial diameter [11, 35]. As a consequence of this compensation, the arterial compliance is usually maintained within normal range, and the distensibility of capacitive arteries is only moderately decreased (Table 2). In uremic patients, the abnormal arterial stiffening is observed principally in younger subjects, since with aging, the effects of age predominate over those of uremia [12]. Moreover, in many older ESRD patients, vascular nephropathies occur, and in these subjects, the arterial alterations are more related to original arterial disease than uremia per se. HEMODYNAMIC FACTORS OF ARTERIAL REMODELING IN CHRONIC UREMIA Large arteries, like the aorta or the common carotid artery, are enlarged in ESRD patients in comparison with age-, sex-, and BP-matched control subjects [11, 35, 53]. The internal dimensions of large arteries are influenced by many factors. Several factors are nonspecific for ESRD patients (for example, age, sex, or mean BP), whereas others are more relevant for this patient population (such as blood-flow velocity and systemic blood flow). In ESRD patients, chronic volume/flow overload creates

S-144

Meeus et al: Cardiovascular disease in dialysis patients

Table 2. Arterial parameters in control subjects and end-stage renal disease patients (ESRD) Parameters Age years Gender (⌫/E; ⌫:1; E:2) BSA m2 Systolic blood pressure mm Hg Diastolic blood pressure mm Hg Mean blood pressure mm Hg CCA ⌬P mm Hg CCA diameter mm CCA ⌬Di lm CCA IMT lm CCA compliance m2·kPa⫺1·10⫺7 CCA distensibility kPa⫺1·10⫺3 CCA Einc kPa 103

Controls N ⫽ 82

ESRD N ⫽ 110

48.5 ⫾ 11.6 1.40 ⫾ 0.49 1.87 ⫾ 0.24 146.4 ⫾ 22.2 88.5 ⫾ 14.3 107.9 ⫾ 15.4 50 ⫾ 14 5.7 ⫾ 0.8 370 ⫾ 133 700 ⫾ 104 5.3 ⫾ 2.3 21.1 ⫾ 9.8 0.48 ⫾ 0.20

50.5 ⫾ 14.2 1.37 ⫾ 0.48 1.71 ⫾ 0.21c 149.5 ⫾ 27.3 84.5 ⫾ 14.1 106.9 ⫾ 16.9 58 ⫾ 22b 6.4 ⫾ 0.9c 390 ⫾ 145 782 ⫾ 114c 5.5 ⫾ 2.5 18.0 ⫾ 8.7a 0.63 ⫾ 0.40c

Values are means ⫾ standard deviation. a P ⫽ 0.025 b P ⫽ 0.005 c P ⬍ 0.001 Abbreviations are: BSA, body surface area; CCA, common carotid artery; ⌬P, pulse pressure; ⌬Di, stroke changes in diameter; IMT, intima-media thickness; Einc, incremental elastic modulus.

Fig. 4. Correlation between hematocrit and common carotid artery (CCA) intima media thickness (IMT) in dialysis patients (r ⫽ 0.37; P ⬍ 0.0001).

tensive patients, Laurent et al have shown that decreased arterial distensibility was due to higher distending BP rather than to arterial wall thickening and structural modifications [57]. In ESRD patients, increased IMT is accompanied by an increased Einc. This modification affects elastic and muscular type arteries [11, 52] and is in favor of altered intrinsic elastic properties or major architectural abnormalities, namely fibroelastic intimal thickening, calcification of elastic lamellae, and ground substance [58, 59]. The reason for uremia-associated changes in elastic modulus is not clear, and several nonhemodynamic factors have been implicated. NONHEMODYNAMIC FACTORS AND ARTERIAL REMODELING IN ESRD PATIENTS Fig. 3. Correlation between hematocrit and common carotid artery (CCA) diameter in dialysis patients (r ⫽ 0.35; P ⬍ 0.0001).

conditions for arterial remodeling (Fig. 3) [54]. This finding has been supported by cross sectional studies showing a relationship between the diameters of the aorta and common carotid artery and LV outflow velocity integral and/or stroke volume [11, 14]. Unlike in BP- and agematched nonuremic patients, the arterial intima-media thickness (IMT) is increased in ESRD patients [11, 13, 52]. According to the Laplace’s law, an increase in IMT is proportional to changes in diameter and is partially influenced by the same hemodynamic alterations as those influencing arterial diameter (Fig. 4). In ESRD, the increase in arterial IMT is associated with decreased arterial distensibility, increased PWV, and an early return of wave reflections [11, 53–56]. In essential hyper-

Arterial remodeling is already observed in patients at the start of renal replacement therapy and is comparable in patients on peritoneal dialysis and patients treated by hemodialysis (Table 3). This suggests that nonhemodynamic factors could play an important role in the pathophysiology of vascular complications. As shown experimentally, the endothelium influences the mechanical and geometric properties of large arteries, and removing the endothelium causes an increase in arterial diameter [60]. Endothelial function is altered in ESRD patients [61–63], and these alterations are associated with arterial remodeling [36]. The role of endothelin in ESRD patients was suggested by Demuth et al, who showed an association between carotid artery IMT and high circulating levels of endothelin-1 [25]. Hyperhomocysteinemia has been recognized as an important vascular risk factor in the general population [64] and was associated with increased arterial stiffness [65]. The elevation of plasma total homocysteine (tHcy) in ESRD patients has also been

S-145

Meeus et al: Cardiovascular disease in dialysis patients Table 3. Arterial parameters in hemodialyzed patients (HD) and patients on peritoneal dialysis (PD) Parameters

HD N ⫽ 95

PD N ⫽ 15

Age years Gender (⌫/E; ⌫:1; E:2) BSA m2 Systolic blood pressure mm Hg Diastolic blood pressure mm Hg Mean blood pressure mm Hg CCA ⌬P mm Hg CCA diameter mm CCA ⌬Di lm CCA IMT lm CCA compliance m2·kPa⫺1·10⫺7 CCA distensibility kPa⫺1·10⫺3 CCA Einc kPa 103 Duration of replacement therapy months

50 ⫾ 15 1.37 ⫾ 0.51 1.68 ⫾ 0.20 148 ⫾ 27 85.4 ⫾ 13.2 107.0 ⫾ 16.3 57 ⫾ 22 6.4 ⫾ 0.9 394 ⫾ 137 770 ⫾ 118 5.7 ⫾ 2.5 18.3 ⫾ 8.6 0.60 ⫾ 0.40

55 ⫾ 14 1.50 ⫾ 0.48 1.78 ⫾ 0.24 153 ⫾ 29 85.0 ⫾ 14.0 108.0 ⫾ 17.0 63 ⫾ 23 6.2 ⫾ 1.0 343 ⫾ 192 800 ⫾ 101 4.9 ⫾ 3.3 17.2 ⫾ 12.0 0.75 ⫾ 0.45

86 ⫾ 78

22 ⫾ 14a

Values are means ⫾ standard deviation. a P ⬍ 0.001 Abbreviations are: BSA, body surface area; CCA, common carotid artery; ⌬P, pulse pressure; ⌬Di, stroke changes in diameter; IMT, intima-media thickness; Einc, incremental elastic modulus.

recognized as an important atherogenic vascular risk factor in hemodialysis patients and kidney transplant recipients [66, 67]. Nevertheless, in ESRD patients, the crosssectional studies have not convincingly shown the type of structural or functional alterations associated with hyperhomocysteinemia. Hyperhomocysteinemia principally affects atherothrombosis, and its role in nonatheromatous arterial remodeling is not clear. In the study by Blacher et al, elevated plasma tHcy levels were associated with lower limb artery stiffness, but not with stiffening of major capacitive arteries like the aorta or carotid artery [68]. While the published data agree that smoking is a factor associated with arterial wall hypertrophy and stiffening in ESRD patients [11, 13], no consistent and constant associations could be established between arterial remodeling and common vascular risk factors. An association between arterial alterations and low highdensity lipoprotein cholesterol or high intermediate density lipoprotein (IDL) was found in some studies [53, 55, 69]. The most frequently observed factors associated with arterial stiffening in ESRD seem to be alterations in calcium and phosphate metabolism and parathyroid activity [69–71]. In hemodialyzed patients, aortic PWV was found to be associated with mediacalcinosis of conduit arteries and increased calcium-phosphate product [53, 55]. Kawagishi et al reported that a high phosphorus level was associated with carotid artery intima-media thickening (IMT), while increased serum parathyroid hormone was a risk factor for increased wall thickness of femoral arteries [13]. Studying renal transplant recipients, Barenbrock et al observed an association between high parathyroid hormone levels and decreased common carotid artery distensibility [71].

CLINICAL CONSEQUENCES OF ARTERIAL REMODELING IN ESRD PATIENTS The arterial changes in ESRD are responsible for an increased systolic and pulse pressures [2, 11, 72]. In the general population, pulse pressure has been shown to be a strong predictor for the risk of coronary heart disease and cardiovascular complications [73–75]. Blacher et al applied logistic regression and Cox analyses to the characteristics of hemodialyzed patients and identified aortic distensibility (aortic PWV) as a strong and independent predictor of cardiovascular and overall mortality [76]. PWV is a complex parameter integrating arterial geometry and intrinsic elastic properties described by the Moens-Korteweg equation PWV2 ⫽ Eh/2r␳ where E is the elastic modulus (Einc); r is the radius; h is the wall thickness, and ␳ is the fluid density [45]. Based on Cox analyses, Blacher et al have shown that the principal “hemodynamic” predictors of cardiovascular and allcause mortality in ESRD were the elastic modulus and dilation of arteries, that is, generalized arterial disease [77]. Dialysis by itself does not improve arterial distensibility [78], and some studies indicate that arterial function worsens with the time on dialysis [13, 70]. In older essential hypertensive nonuremic subjects, the long-term antihypertensive therapy induces reverse remodeling with regression of arterial wall hypertrophy and improvement of the arterial system viscoelastic properties [79]. Until now, such controlled studies have not been available in ESRD patients. During recent years, a few controlled studies aimed at examining the effect of antihypertensive drugs on the function of large arteries have been conducted on ESRD patients on hemodialysis. It has been shown that calcium-channel blockers lowered BP and decreased aortic and femoral PWV [80]. The same effect on arterial distensibility was observed by ACE inhibitors [23, 81]. However, these studies did not conclude whether the improvement of elastic properties was the consequence of the lowered BP or was due to reverse remodeling and changes in the intrinsic properties of arterial walls. In conclusion, besides the cardiovascular risk factors present in the general population, the chronic pressure and volume overload are the principal hemodynamic factors associated with cardiac and vascular remodeling in ESRD patients on hemodialysis. Cardiac and vascular alterations evolve in parallel and are tightly interrelated. LVH and arteriosclerosis are independent risk factors for overall and cardiovascular mortality in dialysis patients. LVH can be partially reversed by the control of anemia and BP. Presently available data are insufficient to propose efficient therapeutical intervention for reversal of arterial alterations, and controlled studies aimed at the prevention and/or correction of arterial abnormalities in ESRD patients are needed.

S-146

Meeus et al: Cardiovascular disease in dialysis patients

Reprint requests to Ge´rard M. London, M.D., Hopital Manhes, 8 Grande Rue, Fleury-Me´rogis, 91700, France. E-mail: [email protected]

23.

REFERENCES 1. U.S. Renal Data System: USRDA 1991 Annual Report. The National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, 1991 2. Raine AEG, Margreiter R, Brunner FP, Ehrich JHH, Geelings W, Landais P, Loirat C, Mallick NP, Selwood NH, Tufveson G, Valderrabano F: Report on management of renal failure in Europe, XXII, 1991. Nephrol Dial Transplant 7(Suppl 2):S7–S35, 1992 3. Rostand RG, Kirk KA, Rutsky EA: Dialysis ischemic heart disease: Insight from coronary angiography. Kidney Int 25:653–659, 1984 4. Harnett JD, Foley RN, Kent GM, Barre PE, Murray D, Parfrey PS: Congestive heart failure in dialysis patients: Prevalence, incidence, prognosis and risk factors. Kidney Int 47:884–890, 1995 5. Parfrey PS, Foley RN, Harnett JD, Kent MG, Murray DC, Barre PE: Outcome and risk factors of ischemic heart disease in chronic uremia. Kidney Int 49:1428–1434, 1996 6. London GM, Marchais SJ, Gue´rin AP, Fabiani F, Me´tivier F: Cardiovascular function in hemodialysis patients, in Advances in Nephrology (vol 20), edited by Gru¨nfeld JP, Bach JF, FunckBrentano JL, Maxwell MH, St. Louis, Mosby Year Book Publishers, 1991, pp 249–273 7. Harnett JD, Kent GM, Barre PE, Taylor R, Parfrey PS: Risk factors for the development of left ventricular hypertrophy in a prospective followed cohort of dialysis patients. J Am Soc Nephrol 4:1486–1490, 1994 8. London GM, Parfrey PS: Cardiac disease in chronic uremia: Pathogenesis. Adv Ren Replace Ther 4:194–211, 1997 9. Silberberg J, Barre PE, Prichard SS, Sniderman AD: Impact of left ventricular hypertrophy on survival in end-stage renal disease. Kidney Int 36:286–290, 1989 10. Roig E, Betriu A, Castaner A, Magrina J, Sanz G, NavarraLopez F: Disabling angina pectoris with normal coronary arteries in patients undergoing hemodialysis. Am J Med 71:437–444, 1981 11. London GM, Gue´rin AP, Marchais SJ, Pannier B, Safar ME, Day M, Metivier F: Cardiac and arterial interactions in end-stage renal disease. Kidney Int 50:600–608, 1996 12. Barenbrock M, Spieker C, Laske V, Rahn K-H: Studies of the vessel wall properties in hemodialysis patients. Kidney Int 45:1397– 1400, 1994 13. Kawagishi T, Nishizawa Y, Konishi T, Kawasaki K, Emoto M, Shoji T, Tabata T, Inoue T, Morii H: High-resolution B-mode ultrasonography in evaluation of atherosclerosis in uremia. Kidney Int 48:820–826, 1995 14. London GM, Dru¨eke TB: Atherosclerosis and arteriosclerosis in chronic renal failure. Kidney Int 51:1678–1695, 1995 15. Grossman W: Cardiac hypertrophy: Useful adaptation or pathological process? Am J Med 69:576–584, 1980 16. Katz AM: Cardiomyopathy of overload: a major determinant of prognosis in congestive heart failure. N Engl J Med 322:100–110, 1990 17. Morgan HE, Baker KM: Cardiac hypertrophy: Mechanical, neural, and endocrine dependence. Circulation 83:13–25, 1991 18. Dzau VJ: The role of mechanical and humoral factors in growth regulation of vascular smooth muscle and cardiac myocytes. Curr Opin Nephrol Hypertens 2:27–32, 1993 19. Foley RN, Parfrey PS, Harnett JD, Kent GM, Martin CJ, Murray DC, Barre PE: Clinical and echocardiographic disease in patients starting ESRD therapy. Kidney Int 47:186–192, 1995 20. London GM, Gue´rin AP, Marchais SJ: Pressure-overload cardiomyopathy in end-stage renal disease. Curr Opin Nephrol Hypertens 8:179–186, 1999 21. Amann K, Wiest G, Klaus G, Ritz E, Mall G: The role of parathyroid hormone in the genesis of interstitial cell activation in uremia J Am Soc Nephrol 4:1814–1819, 1994 22. Amann K, Kronenberg G, Gehlen F, Wessels S, Orth S, Mu¨nter K, Ehmke H, Mall G, Ritz E: Cardiac remodelling in experimental

24.

25. 26. 27.

28. 29. 30.

31. 32.

33. 34.

35.

36.

37. 38. 39.

40.

41.

42.

renal failure—An immunohistochemical study. Nephrol Dial Transplant 13:1958–1966, 1998 London GM, Pannier B, Gue´rin AP, Marchais SJ, Safar ME, Cuche JL: Cardiac hypertrophy, aortic compliance, peripheral resistance, and wave reflection in end-stage renal disease: Comparative effects of ACE inhibition and calcium channel blockade. Circulation 90:2786–2796, 1994 Vlahakos DV, Hahalis G, Vassilakos P, Marathias KP, Geroulanos S: Relationship between left ventricular hypertrophy and plasma renin activity in chronic hemodialysis patients. J Am Soc Nephrol 8:1764–1770, 1997 Demuth K, Blacher J, Gue´rin AP, Benoit M-O, Moatti N, Safar ME, London GM: Endothelin and cardiovascular remodelling in end-stage renal disease. Nephrol Dial Transplant 13:375–383, 1998 Mall G, Huther W, Schneider J, Lundin P, Ritz E: Diffuse intramyocardial fibrosis in uraemic patients. Nephrol Dial Transplant 5:39–44, 1990 Amann K, To¨rnig J, Flechtenmacher Ch, Nabokov A, Mall G, Ritz E: Blood-pressure-independent wall thickening of intramyocardial arterioles in experimental uremia: Evidence for a permissive action of PTH. Nephrol Dial Transplant 10:2043–2048, 1995 Amann K, Breitbach M, Ritz E, Mall G: Myocyte/capillary mismatch in the heart of uremic patients. J Am Soc Nephrol 9:1018– 1022, 1998 Katz AM: The cardiomyopathy of overload: An unnatural growth response in the hypertrophied heart. Ann Intern Med 121:363–371, 1994 London GM, Fabiani F, Marchais SJ, de Vernejoul M-Ch, Gue´rin AP, Safar ME, Metivier F, Llach F: Uremic cardiomyopathy: An inadequate left ventricular hypertrophy. Kidney Int 31:973–980, 1987 Gafter U, Battler A, Eldar M, Zevin D, Neufeld HN, Levi J: Effect of hyperparathyroidism on cardiac function in patients with end-stage renal disease. Nephron 41:30–33, 1985 Zucchelli P, Santoro A, Zucchelli A, Spongano M, Ferrari G: Long-term effects of parathyroidectomy on cardiac and autonomic nervous system functions in haemodialysis patients. Nephrol Dial Transplant 3:45–50, 1988 Fellner SK, Lang RM, Neumann A, Bushinsky DA, Borow KM: Parathyroid hormone and cardiac performance in dialysis patients. Am J Kidney Dis 18:320–325, 1991 Ehmke H, Faulhaber J, Mu¨nter K, Kirchengast M, Wiesner RJ: Chronic ETA receptor blockade attenuates cardiac hypertrophy independently of blood pressure effects in renovascular hypertensive rats. Hypertension 33:954–960, 1999 Savage T, Clarke AL, Giles M, Tomson CRV, Raine AEG: Calcified plaque is common in the carotid and femoral arteries of dialysis patients without clinical vascular disease. Nephrol Dial Transplant 13:2004–2012, 1998 Pannier B, Gue´rin AP, Marchais SJ, Me´tivier F, Safar ME, London GM: Postischemic vasodilation, endothelial activation and cardiovascular remodeling in end-stage renal disease. Kidney Int 57:1091–1099, 2000 Joles JA, Willekes-Koolschijn N, Koomans HA: Hypoalbuminemia causes high blood viscosity by increasing red cell lysophosphatidylcholine. Kidney Int 52:761–770, 1997 Minamiyama Y, Takemura S, Inoue M: Albumin is an important vascular tonus regulator as a reservoir of nitric oxide. Biochem Biophys Res Commun 225:112–115, 1996 Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE: The impact of anemia on cardiomyopathy, morbidity and mortality in end-stage renal disease. Am J Kidney Dis 28:53–61, 1996 Levin A, Thompson CR, Ethier J, Carlisle EJF, Tobe S, Mendelssohn D, Burgess E, Jindal K, Barrett B, Singer J, Djurdjev O: Left ventricular mass index increase in early renal disease: Impact of decline in hemoglobin. Am J Kidney Dis 34:125– 134, 1999 Silberberg J, Racine N, Barre P, Sniderman AD: Regression of left ventricular hypertrophy in dialysis patients following correction of anemia with recombinant human erythropoietin. Can J Cardiol 6:1–4, 1990 Cannella G, La Canna G, Sandrini M, Gaggiotti M, Nordio

Meeus et al: Cardiovascular disease in dialysis patients

43. 44.

45. 46. 47. 48. 49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

G, Movilli E, Mombelloni S, Visioli O, Maiorca S: Reversal of left ventricular hypertrophy following recombinant human erythropoietin treatment of anaemic dialysed uremic patients. Nephrol Dial Transplant 6:31–37, 1991 Fellner SK, Lang RM, Neumann A, Korcarz C, Borow KM: Cardiovascular consequences of correction of the anemia of renal failure with erythropoietin. Kidney Int 44:1309–1315, 1993 Dahan M, Siohan P, Viron B, Michel C, Paillole C, Gourgon R, Mignon F: Relationship between left ventricular hypertrophy, myocardial contractility, and load conditions in hemodialysis patients: An echocardiographic study. Am J Kidney Dis 30:780–785, 1997 Nichols WW, O’Rourke MF: Vascular impedance, in McDonald’s Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles (4th ed), London, Edward Arnold Publisher, 1998 Safar ME, Levy BI, Laurent S, London GM: Hypertension and the arterial system: Clinical and therapeutic aspects. J Hypertens 8(Suppl 7):S113–S119, 1990 O’Rourke MF, Kelly RP: Wave reflexion in the systemic circulation and its implications in ventricular function. J Hypertens 11:327– 337, 1993 Watanabe H, Ohtsuka S, Kakihana M, Sugishita Y: Coronary circulation in dogs with an experimental decrease in aortic compliance. J Am Coll Cardiol 21:1497–1506, 1993 Marchais SJ, Gue´rin AP, Pannier BM, Levy BI, Safar ME, London GM: Wave reflections and cardiac hypertrophy in chronic uremia: Influence of body size. Hypertension 22:876–883, 1993 Lindner A, Charra B, Sherrard D, Scribner BM: Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 290:697–702, 1974 Vincenti F, Amend WJ, Abele J, Feduska NJ, Salvatierra O Jr: The role of hypertension in hemodialysis-associated atherosclerosis. Am J Med 68:363–369, 1980 Mourad JJ, Girerd X, Boutouyrie P, Laurent S, Safar ME, London GM: Increased stiffness of radial artery wall material in end-stage renal disease. Hypertension 30:1425–1430, 1997 London GM, Marchais SJ, Safar ME, Genest AF, Gue´rin AP, Metivier F, Chedid K, London AM: Aortic and large artery compliance in end-stage renal disease. Kidney Int 37:137–142, 1990 Girerd X, London G, Boutouyrie P, Mourad JJ, Laurent S, Safar M: Remodelling of radial artery and chronic increase in shear stress. Hypertension 27:799–803, 1996 Saito Y, Shirai K, Uchino J, Okazawa M, Hattori Y, Yoshida T, Yoshida S: Effect of nifedipine administration on pulse wave velocity (PWV) of chronic hemodialysis patients: 2 year trial. Cardiovasc Drug Ther 4:987–990, 1990 London GM, Gue´rin AP, Pannier B, Marchais SJ, Benetos A, Safar ME: Increased systolic pressure in chronic uremia: Role of arterial wave reflections. Hypertension 20:10–19, 1992 Laurent S, Girerd X, Mourad JJ, Lacolley P, Beck L, Boutouyrie P, Mignot J-P, Safar M: Elastic modulus of the radial artery wall material is not increased in patients with essential hypertension. Arterioscler Thromb 14:1223–1231, 1994 Amann K, Neusu¨ß R, Ritz E, Wiest G, Mall G: Changes of vascular architecture independent of blood pressure in experimental uremia. Am J Hypertens 8:409–417, 1995 Ibels LS, Alfrey AL, Huffer WE, Craswell PW, Anderson JT, Weil R: Arterial calcification and pathology in uremic patients undergoing dialysis. Am J Med 66:790–796, 1979 Le´vy BI, Benessiano J, Poitevin P, Safar ME: Endotheliumdependent mechanical properties of carotid artery in WKY and SHR: Role of angiotensin converting enzyme inhibition. Circ Res 66:321–328, 1990 Joannides R, Bakkali EH, Le Roy F, Rivault O, Godin M, Moore N, Fillastre J-P, Thuilliez CH: Altered flow-dependent vasodilatation of conduit arteries in maintenance haemodialysis. Nephrol Dial Transplant 12:2623–2628, 1997 Gris JC, Branger B, Ve´cina F, Sabadani BA, Fourcade J, Schved JF: Increased cardiovascular risk factors and features of endothelial dysfunction in dialyzed uremic patients. Kidney Int 46:807–813, 1994 van Guldener C, Janssen MJF, Lambert J, Steyn M, Donker

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78. 79.

80.

81.

S-147

AJN, Stehouwer CDA: Endothelium-dependent vasodilatation is impaired in peritoneal dialysis patients. Nephrol Dial Transplant 13:1782–1786, 1998 Selhub J, Jacques PF, Bostom AG, D’Agostino RB, Wilson PWF, Belanger AF, O’Leary DH, Wolf PA, Schaefer EJ, Rosenberg IH: Association between plasma homocysteine concentration and extracranial carotid-artery stenosis. N Engl J Med 332:286– 291, 1995 Bortolotto LA, Safar ME, Billaud E, Lacroix C, Asmar R, London GM, Blacher J: Plasma homocysteine, aortic stiffness and renal function in hypertensive patients. Hypertension 34(4 Pt 2):889–892, 1999 Bostom AG, Lathrop L: Hyperhomocysteinemia in end-stage renal disease: Prevalence, etiology, and potential relationship to arteriosclerotic outcomes. Kidney Int 52:10–20, 1997 Bostom AG, Shemin D, Verhoef P, Nadeau MR, Jacques PF, Selhub J, Dworkin L, Rosenberg IH: Elevated fasting total plasma homocysteine levels and cardiovascular disease outcomes in maintenance dialysis patients: A prospective study. Arterioscler Thromb Vasc Biol 17:2554–2558, 1997 Blacher J, Demuth K, Guerin AP, Safar ME, Moatti N, London GM: Influence of biochemical alterations on arterial stiffness in patients with end-stage renal disease. Arterioscler Thromb Vasc Biol 18:535–541, 1998 Nishizawa Y, Shoji T, Kawagishi T, Morii H: Atherosclerosis in uremia: Possible roles of hyperparathyroidism and intermediate density lipoprotein accumulation. Kidney Int 52(Suppl 62):S90– S92, 1997 Burdick L, Periti M, Salvaggio A, Bertoli S, Mangiarotti R, Castagnone D, Anguissola G: Relation between carotid artery atherosclerosis and time on dialysis: A non-invasive study in vivo. Clin Nephrol 42:121–126, 1994 Barenbrock M, Hausberg M, Kosch M, Kisters K, Hoeks APG, Rahn K-H: Effect of hyperparathyroidism on arterial distensibility in renal transplant recipients. Kidney Int 54:210–215, 1998 Mailloux LU, Haley WE: Hypertension in the ESRD patients: Pathophysiology, therapy, outcomes, and future directions. Am J Kidney Dis 32:705–719, 1998 Benetos A, Safar M, Rudnichi A, Smulyan H, Richard JL, Ducimetiere P: Pulse pressure: A predictor of long-term cardiovascular mortality in a French male population. Hypertension 30:1410– 1415, 1999 Mitchell GF, Moye LM, Braunwald E, Rouleau JL, Bernstein V, Geltman EM: Sphygmomanometrically determined pulse pressure is a powerful independent predictor of recurrent events after myocardial infarction in patients with impaired left ventricular function. Circulation 96:4254–4260, 1997 Franklin SS, Khan SA, Wong ND, Larson MG, Levy D: Is pulse pressure useful in predicting risk for coronary heart disease? The Framingham heart study. Circulation 100:354–360, 1999 Blacher J, Gue´rin AP, Pannier B, Marchais SJ, Safar ME, London GM: Impact of aortic stiffness on survival in end-stage renal disease. Circulation 99:2434–2439, 1999 Blacher J, Pannier B, Guerin AP, Marchais SJ, Safar ME, London GM: Carotid arterial stiffness as a predictor of cardiovascular and all-cause mortality in end-stage renal disease. Hypertension 32:570–574, 1998 Marchais S, Gue´rin A, Safar M, London G: Arterial compliance in uremia. J Hypertens 7(Suppl 6):S84–S85, 1989 Girerd X, Giannattassio C, Moulin C, Safar M, Mancia G, Laurent S: Regression of radial artery wall hypertrophy and improvement of carotid compliance after long-term antihypertensive treatment in elderly patients. J Am Coll Cardiol 31:1063–1073, 1998 London GM, Marchais SJ, Gue´rin AP, Me´tivier F, Safar ME, Fabiani F, Froment L: Salt and water retention and calcium blockade in uremia. Circulation 82:105–113, 1990 London GM, Pannier B, Vicaut E, Gue´rin AP, Marchais SJ, Safar ME, Cuche JL: Antihypertensive effects and arterial haemodynamic alterations during angiotensin converting enzyme inhibition J Hypertens 14:1139–1146, 1996