Left ventricular alterations and end-stage renal disease

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1 Nephrol Dial Transplant (2002) 17 wsuppl 1x: Left ventricular alterations and end-stage renal disease Gerard M. London Centre Hospitalier FH MANHES, Fleury-Mérogis, France Abstract The prevalence of left ventricular (LV) changes, especially LV hypertrophy (LVH), is high among patients with chronic kidney disease and end-stage renal disease (ESRD). Ventricular enlargement usually is associated with normal systolic function and increased stroke and cardiac index. In the absence of intrinsic heart disease, LV enlargement is most probably attributable to chronic volumeuflow overload associated with anaemia, the presence of arteriovenous shunts, and sodium and water retention. In ESRD patients, hypertension is also a leading cause of LVH, but structural LV changes and myocardial fibrosis may also be due to non-haemodynamic factors such as angiotensin II, parathyroid hormone, endothelin, aldosterone, increased sympathetic nerve discharge and increased plasma catecholamines. To improve the clinical outcomes in ESRD, it is essential to prevent LVH and its complications by correcting the factors that contribute to flow and pressure overload, including anaemia. Keywords: anaemia; cardiac disease; haemodynamic factors; hypertension; kidney disease; left ventricular hypertrophy Introduction Cardiovascular complications are the leading cause of death in patients with end-stage renal disease (ESRD), accounting for 40% of deaths in these patients w1x. Ischaemic heart disease, heart failure and cardiomyopathy are the most frequent causes of cardiac death in ESRD w2 5x. Cross-sectional studies have shown that left ventricular hypertrophy (LVH) is the most frequent cardiac alteration in ESRD and is an independent risk factor for survival w6x. Correspondence and offprint requests to: Gerard M. London, Centre Hospitalier FH MANHES, 8 Grande Rue, Fleury-Mérogis, 91700, France. Tel: q , fax: q , glondon@club-internet.fr Haemodynamic factors and the development of left ventricular hypertrophy LVH is an adaptive response to an increase in cardiac work, which may be due to volume anduor pressure overload w7x. Factors determining stroke volume The work the heart performs per ventricular beat (stroke work) equals stroke volume multiplied by left ventricular (LV) pressure w8x. The stroke volume depends on the energy of cardiomyocyte contraction and on the force opposing the ejection of blood (ventricular afterload). The energy of cardiomyocyte contraction depends on the preload (stretching of the myocytes during diastole) and myocyte contractility. Starling s law states that, for a given contractility, ventricular output increases in relation to preload. High stroke volume can result from increased LV filling, due to either increased venous return or increased ventricular compliance, and increased LV contractility. Factors determining left ventricular pressure Afterload, which determines LV pressure, depends mainly on factors that oppose LV ejection (i.e. aortic impedance). Aortic impedance depends on the following factors (i) Peripheral resistance, which is related to the tone and number of arterioles, and blood viscosity. Peripheral resistance is a determinant of mean blood pressure. It represents the opposition to a steady component of blood flow (i.e. cardiac output). (ii) The stiffness of the aorta and large arteries, which determines pulse pressure amplitude and the propagative properties of the arterial system. (iii) Inertial forces, due to the mass of the blood in the arterial tree and left ventricle, which increases with the internal dimensions of the arterial system (inertance) w8,9x. # 2002 European Renal Association European Dialysis and Transplant Association

2 30 G. M. London Influence of wall stress on left ventricular hypertrophy Myocardial oxygen consumption and energy expenditure increase with stroke work. For the same stroke work, energy expenditure increases with blood pressure, because the heart is more efficient when an increment in work results from an increase in stroke volume than when it results from increased blood pressure. This phenomenon is related to changes in LV wall stress (tensile stress) during the cardiac cycle. The relationship between wall stress and pressure is influenced by the size of the ventricle. According to Laplace s law, the tensile stress (s) is directly proportional to intraventricular pressure (P) and radius (r) and inversely proportional to ventricular wall thickness (h) according to the formula: ssp ru2h. An increase in wall thickness therefore reduces the tension developed during systole by each individual cardiomyocyte. By distributing tension among a greater number of sarcomeres, LVH reduces the load on each individual muscle fibre and regulates cardiac efficiency and oxygen consumption w7x. In the case of pressure and volume overload, the initiating signals for development of LVH include myocardial stretch and cell deformation (which increases parietal tensile stress). Patterns of left ventricular hypertrophy LVH usually develops in a pattern specific to the initiating mechanical stress; volume or pressure overload (Figure 1) w10,11x. Morphological differences between pressure- and volume-induced LVH are associated with distinct myocyte phenotypes and differential induction of peptide growth factor mrnas. (i) Pressure overload results in parallel addition of new sarcomeres with an increase of LV wall thickness at normal chamber radius (concentric hypertrophy). (ii) Volume overload results primarily in the addition of new sarcomeres in series and, secondarily, in the addition of sarcomeres in parallel. The addition of new sarcomeres results in an enlargement of the LV chamber, with increased wall thickness just sufficient to counterbalance the increased radius (eccentric hypertrophy) w7x. Non-haemodynamic factors and the development of left ventricular hypertrophy Non-haemodynamic (neurohumoral) factors are also important in the development of LVH w11x. Mechanical and neurohumoral factors independently can activate effectors of intracellular signalling (such as stretch-sensitive membrane ion channels and receptors), leading to increased activity of second messengers and protein kinases. These agents enhance gene expression for contractile proteins, re-expression of a fetal gene programme and expression of protooncogenes encoding growth factors and growth factor receptors w11,12x. In general, endogenous vasoconstrictors act as growth promoters, and endogenous vasodilators act as growth inhibitors. Beneficial and detrimental consequences of left ventricular hypertrophy In healthy humans, cardiac hypertrophy is a beneficial physiological process that occurs during growth and maturation of children or as a result of intense physical exercise. The size of the chamber changes in proportion to its workload and to body dimensions. The development and characteristics of cardiac hypertrophy are influenced by several other factors such as age, gender, race and the co-existent or related diseases w7x. Fig. 1. Hypothesis relating wall stress to patterns of concentric and eccentric LVH. (Adapted from w7x.)

3 Left ventricular alterations and end-stage renal disease In circumstances of pathological overload, LVH has both beneficial and detrimental effects. The heart benefits initially from a phase of compensated adaptive hypertrophy, in which normal systolic function is maintained. The increased number of sarcomeres and increased wall thickness increase the working capacity of the left ventricle while keeping parietal tensile stress stable, sparing energy. However, sustained overload leads progressively to a maladaptive hypertrophic response characterized by the dominance of deleterious effects and development of overload cardiomyopathy and heart failure w13x. During this maladaptive phase, the overloaded myocardial cells have an increased rate of energy expenditure. There is an imbalance between energy expenditure and production, resulting in chronic energy deficit and myocyte death. Cell death in the overloaded ventricle further increases the burden on surviving myocytes, creating a vicious circle with progressive cardiosclerosis and heart failure w14x. The pathogenesis of chronic energy deficit is complex, and includes impaired coronary circulation and decreased coronary reserve w15,16x. Although myocyte death may be due to energy starvation, there is growing evidence that abnormal induction of the expression of proto-oncogenes contributes to cardiomyopathy. Proto-oncogenes promote and regulate cell proliferation and differentiation. Activation of growth factors stimulates proliferation and activity of cardiac fibroblasts, resulting in myocardial fibrosis: a rapid increase in collagen synthesis and a disproportionate increase in extracellular matrix w17x, which impairs diastolic filling. Myocardial fibrosis is more marked in pressure overload than in volume overload and is favoured by factors such as senescence, ischaemia, catecholamines, angiotensin II and aldosterone w17 19x. Another factor related to abnormal diastolic function in the hypertrophied myocardium are lusitropic abnormalities (delayed relaxation), resulting from slower re-uptake of calcium by the sarcoplasmic reticulum. The prolongation of cytosolic calcium transients increases the duration of the action potential. Delayed after-depolarization contributes to arrhythmias, which are also favoured by conduction abnormalities linked to fibrosis and hypertrophy w20,21x. Characteristics of left ventricular hypertrophy in end-stage renal disease LVH is common among patients with ESRD w22,23x, and occurs early in the course of chronic kidney disease. In one prospective study, 74% of patients starting dialysis had LVH, and high LV mass index was an independent predictor of death after 2 years of treatment w23x. Classifying LVH into eccentric or concentric types sometimes is difficult in patients on dialysis, as cyclic variations in extracellular fluid volume and electrolyte balance mean that steady-state conditions are not achieved. The internal dimensions of the left ventricle are influenced by volume status. Reduction of blood volume during a haemodialysis session decreases LV diameter and induces acute changes in LV wall thickness (increasing wall to lumen ratio) w24x. In general, however, the increase in LV mass in ESRD patients is due to a mild enlargement of the LV enddiastolic diameter and increased LV wall thickness, and combines the features of eccentric and concentric hypertrophy w2,24x. Although haemodynamic factors cannot account entirely for increased LV mass, LVH in ESRD is due principally to a chronic increase in stroke work and LV minute work, resulting from an association of volume and pressure overload w24x. In the absence of intrinsic heart disease, LV enlargement is most probably attributable to chronic volumeuflow overload, associated with three principal factors: anaemia, the presence of arteriovenous shunts and sodium and water retention w24,25x. Anaemia, left ventricular hypertrophy and end-stage renal disease The amount of oxygen (O 2 ) delivered to an organ or tissue is dependent on three factors: (i) haemodynamic factors (i.e. cardiac output and its distribution) (ii) O 2 -carrying capacity of the blood (i.e. haemoglobin level) (iii) O 2 extraction (i.e. the difference in oxygen saturation between arterial and venous blood) w26x. When anaemia is present, haemodynamic and nonhaemodynamic mechanisms attempt to compensate for decreased O 2 delivery. Non-haemodynamic compensatory mechanisms Non-haemodynamic compensatory mechanisms against anaemia include increased erythropoietin production and displacement of the haemoglobin O 2 dissociation curve to the right. This displacement enables a greater release of O 2 from erythrocytes at any partial pressure of O 2 (decreased affinity of haemoglobin for O 2 ) w27x. Decreased affinity is mediated principally by increased 2,3-diphosphoglycerate levels, although other factors such as increased temperature or decreased ph can also play a role. In resting conditions, decreased O 2 affinity may compensate for much of the haemoglobin deficit, limiting the effect of haemodynamic factors w27x. With haemoglobin levels of O10 gudl w28x, or in non-resting conditions, non-haemodynamic compensatory mechanisms are overcome. Compensation for tissue hypoxia must then be achieved by haemodynamic mechanisms (Figure 2), resulting in increased cardiac output and blood flow. 31

4 32 G. M. London Haemodynamic compensatory mechanisms The mechanisms of haemodynamic compensation in ESRD are complex and may include reduction in afterload, increase in preload and increased sympathetic activity (Figure 3) w29x. (i) Reduction in afterload is due to decreased vascular resistance, which in turn results from reduced blood viscosity and arterial dilation. Blood viscosity is reduced because of the decrease in erythrocyte number and reduction in haematocrit. Arterial dilation results from increased arteriolar diameter, the recruitment of new vessels and formation of collaterals w30,31x. (ii) Increase in preload results from increased venous return, due to decreased resistance. Resistance decreases in parallel with the decrease in haematocrit and blood viscosity. Arteriolar vasodilation also facilitates pressure transmission from the arterial system to the venous circulation, creating a favourable pressure gradient for venous return. (iii) Increased sympathetic activity can induce active venoconstriction, favouring cardiac filling. Increased LV performance can, therefore, result from increased preload (via the Frank Starling mechanism) and from changes in the inotropic state w26,32,33x. Clinical consequences of anaemia The severity of cardiac symptoms related to anaemia depends on how quickly anaemia develops and the presence or absence of underlying cardiovascular disorders. Patients without underlying heart disease have few cardiac symptoms, and congestive heart failure occurs only in severe anaemia with haemoglobin levels O5 gudl w26x. However, in the presence of underlying heart disease, especially coronary artery disease, anaemia contributes to a high incidence of cardiovascular complications. In acute or short-lasting anaemia, clinical and haemodynamic changes are reversed when haemoglobin levels are normalized w26x. In chronic anaemia, however, prolonged flowuvolume overload and increased cardiac work lead to progressive cardiac enlargement and LVH w2,4,5,34x. LVH progresses in parallel with changes in haemoglobin level w35x. Correction of anaemia with epoetin alfa can decrease cardiac output and heart rate, and induce at least a partial regression of the LV size w36 39x. Arteriovenous shunts, overhydration, left ventricular hypertrophy and end-stage renal disease The creation of arteriovenous shunts for haemodialysis access is partly responsible for LV dilation and highoutput states in ESRD patients. The presence of an arteriovenous shunt lowers peripheral resistance, and blood pressure is maintained through elevation of cardiac output, via increased heart rate and stroke volume w24x. Cardiomegaly with high-output cardiac insufficiency may therefore occur as a complication of high-flow arteriovenous shunts. However, symptomatic cardiac failure due to arteriovenous shunts alone is uncommon w40x. Interdialytic body weight changes correlate directly with LV mass, as well as with stroke volume, as the internal LV dimensions, stroke volume and end-diastolic pressure are directly related to circulating blood volume w41x. Fig. 2. Haemodynamic changes induced by anaemia.

5 Left ventricular alterations and end-stage renal disease Pressure overload, left ventricular hypertrophy and end-stage renal disease Hypertension is a leading cause of LVH in ESRD patients, and is more closely related to systolic or pulse pressure than to diastolic pressure w24,42,43x. The clinical characteristics of hypertension depend on the dominant factors altering arterial impedance. Increased peripheral resistance is characterized by increased mean blood pressure and diastolic pressure, whereas increased arterial stiffness is characterized by increased systolic pressure and wide pulse pressure, with normal or low diastolic pressure w9x. Peripheral resistance is normal or lower, however, in uncomplicated ESRD, due to the presence of anaemia anduor arteriovenous shunts. In these conditions, mean blood pressure or diastolic pressure do not reflect pressure overload accurately, and LVH is correlated more closely with arterial stiffening and increased inertance. These changes are associated with remodelling of the arterial tree (dilation and wall hypertrophy) w44 47x. Arterial stiffening also results in increased LV afterload, with development of LVH and increased myocardial oxygen demand, and altered coronary perfusion and subendocardial blood flow distribution. Cross-sectional studies have shown that remodelling of central arteries is associated with increased blood flow and flow velocity, due to the high-output state and chronic flow overload, characteristic of ESRD w24,44x. Additional factors influencing left ventricular hypertrophy in end-stage renal disease Experimental and clinical studies demonstrate that various additional factors influence the extent of myocardial fibrosis and the clinical manifestations of LVH (Figure 4) w48x. Interstitial myocardial fibrosis is a prominent finding in the uraemic heart, and is more marked in ESRD patients than in patients with similar LV mass who have diabetes or essential hypertension. Several factors are known to contribute to myocardial fibrosis in ESRD, including angiotensin II, parathyroid hormone, endothelin, aldosterone, increased sympathetic nerve discharge and increased plasma catecholamines w49 53x. Decreased systolic function is observed frequently in ESRD patients who have pre-existent cardiac disease, or who experience sustained and marked haemodynamic overload. In ESRD patients without preexisting cardiac disease, indices of systolic function usually are normal or even increased. In contrast, diastolic filling frequently is altered in dialysis patients w24x. Abnormal ventricular filling in ESRD results from increased LV stiffness due to fibrosis and delayed relaxation w54,55x. Increased LV stiffness is characterized by a marked effect of LV volume changes on LV filling pressure. A small increase in LV volume can thus cause pulmonary congestion, whereas volume depletion can induce a decline in filling pressure, thereby leading to systemic hypotension and haemodynamic instability w56x. Conclusion LVH is common in ESRD patients, and is an independent risk factor for survival. LVH in ESRD patients is related principally to the chronic increase in cardiac work. In the absence of intrinsic heart disease, this increase in cardiac work is due mainly to chronic volumeuflow overload due to anaemia. In patients on dialysis, chronic volumeuflow overload may be compounded by the presence of arteriovenous shunts and by sodium and water retention, exacerbating LV enlargement. Hypertension is also a leading cause of LVH in ESRD patients. 33 Fig. 3. Ventricular vascular interactions in ESRD. (Reproduced with permission from w29x.)

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