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Therapeutic Apheresis and Dialysis 2015; 19(5):427–435 doi: 10.1111/1744-9987.12301 © 2015 The Authors Therapeutic Apheresis and Dialysis © 2015 International Society for Apheresis
Review
Left Ventricular Diastolic Dysfunction in End-Stage Kidney Disease: Pathogenesis, Diagnosis, and Treatment Tetsuya Ogawa, Misato Koeda, and Kosaku Nitta Department of Medicine, Medical Center East and Kidney Center, Tokyo Women’s Medical University, Tokyo, Japan
Abstract: Diastolic dysfunction is frequently observed in end-stage kidney disease (ESKD), and ESKD patients have many risk factors for heart failure (HF), including hypertension, diabetes, and coronary artery disease. Diastolic HF, also called HF with preserved ejection fraction, refers to a clinical syndrome in which patients have symptoms and signs of HF, normal or near normal left ventricular (LV) systolic function, and evidence of diastolic dysfunction manifested by abnormal LV filling and elevated filling pressure. Recent reports suggest that HF
with preserved ejection fraction is more common in hemodialysis patients than HF with low ejection fraction. Diastolic HF in ESKD patients is a strong predictor of death. In this article, we review the information available in the literature on the pathogenesis, diagnosis, and potential treatment strategies of diastolic dysfunction or diastolic HF based on evidence obtained in the general population that is potentially applicable to ESKD patients. Key Words: Dialysis, Diastolic dysfunction, Doppler echocardiography, End-stage kidney disease, Mortality.
In the general population, heart failure (HF) is frequently associated with impaired left ventricular (LV) function. However, as many as 30–40% of all patients with typical symptoms of congestive HF have a normal or slightly reduced LV ejection fraction (EF), and diastolic dysfunction has been implicated as a major contributor, if not the primary cause of the congestive HF in such patients (1). The syndrome of clinical HF with preserved LV systolic function in the absence of cardiac valvular lesions is often referred to as diastolic dysfunction with abnormal LV filling and elevated filling pressure. However, whether diastolic dysfunction is a cause of HF remains a matter of controversy. Diastolic dysfunction is typically observed in hypertensive patients and has a particularly high prevalence in the elderly population (2). Caruana et al. showed that 109 of 159 patients with suspected HF in the absence of LV systolic dysfunction were incorrectly
diagnosed with diastolic HF (3). While investigators may agree that some patients with HF have a normal EF, they doubt that the underlying mechanism is diastolic dysfunction. In some case series, the relations between LV pressure and volume measured by cardiac catheterization have not conformed to the classical pattern of diastolic dysfunction (4). Cardiovascular disease, including HF, is a major cause of death among patients with end-stage kidney disease (ESKD) in Japan (5). As risk factors for HF, i.e. volume expansion, hypertension, diabetes, dyslipidemia, and atherosclerosis are frequently present in patients with chronic kidney disease (CKD) (6). Subclinical diastolic dysfunction has recently been reported to be the most common echocardiographic finding in asymptomatic hemodialysis patients with LV hypertrophy (LVH) (7).The most common factors associated with diastolic dysfunction are aging, hypertension, diabetes, coronary artery disease, LVH and cardiomyopathy. These factors are often associated with the development of myocardial fibrosis and decreased ventricular compliance, which are pathophysiological features of diastolic HF. This article reviews the literature on the pathogenesis, diagnosis, and treatment of diastolic dysfunction or diastolic HF in ESKD patients, based on
Received September 2014; revised December 2014. Address correspondence and reprint requests to Dr Kosaku Nitta, Department of Medicine, Kidney Center, Tokyo Women’s Medical University, Tokyo 162-8666, Japan. Email: knitta@ kc.twmu.ac.jp
427
428
T Ogawa et al.
evidence obtained in the general population that is potentially applicable to CKD patients, including ESKD patients. PATHOGENESIS OF DIASTOLIC DYSFUNCTION The majority of patients with diastolic dysfunction exhibit abnormal active myocardial relaxation and passive ventricular stiffness that contribute to abnormal ventricular filling in diastole and shift the normal ventricular pressure-volume curve upward and to the left, thereby resulting in a higher LV filling pressure for any given filling volume (8). In addition, neurohormonally mediated increases in venous tone and systemic arterial pressure may contribute to shifting blood to the central circulation, and thereby further increase LV filling pressure. When LV diastolic function is impaired, cardiac output is reduced, because the LV is not filled enough in diastole due to LV inflow obstruction. By contrast, to compensate for reduced cardiac output, increasing the inflow pressure to the LV and consequently LV end-diastolic pressure becomes necessary, and that in turn increases left atrial pressure. As a result, LV dysfunction tends to cause pulmonary congestion (9). The end-systolic pressure-volume relationship in diastolic dysfunction is the same as in a normal heart,
but the end-diastolic pressure-volume relationship shifts upwards (Fig. 1a) (10), and LV end-diastolic pressure rises as a result. When an abrupt increase in blood pressure occurs, since the pressure-volume curve shifts to the upper right without any decrease in Emax (absolute index of contractibility), when an abrupt increase in blood pressure occurs, pulmonary congestion is induced by the significant increase in LV end-diastolic pressure (Fig. 1b). Left ventricular contractility appears to be considered normal in diastolic dysfunction; however, the contractile velocity in systole measured by tissue Doppler echocardiography is low in both systolic and diastolic dysfunction (11), and local contractility in the longitudinal direction is known to be impaired in diastolic HF (12). Recent findings suggest that contractility decreases even in diastolic HF at the myocardial level. In contrast, diastolic function is also impaired in systolic HF, and it has been shown to decrease exercise tolerance and to be one of the determinants of the outcome (13). Diastolic and systolic HF are not considered separate, independent entities, and the single syndrome hypothesis of HF shown in Figure 2 is advocated. In that hypothesis, HF is a single continuous disease spectrum and systolic and diastolic HF are phenotypes at two extremes. HF with LVEF of 45 to 50% would be located in the middle of the continuum of the disease spectrum.
FIG. 1. (a) The end-diastolic pressure-volume curve shifts upwards in diastolic heart failure, followed by a rise in left ventricular (LV) end-diastolic pressure. (b) When an abrupt increase in blood pressure occurs, the pressure-volume curve shifts to the upper right without any decrease in Emax in patients with diastolic dysfunction.
Ther Apher Dial, Vol. 19, No. 5, 2015
© 2015 The Authors Therapeutic Apheresis and Dialysis © 2015 International Society for Apheresis
Diastolic Dysfunction in ESKD
FIG. 2. Diastolic and systolic heart failure are not considered separate, independent entities.
By contrast, some investigators have reported that diastolic dysfunction should be widely recognized as a determinant of the pathophysiology in HF (14). LV systolic dysfunction occurs in some patients with diastolic HF. The terms “diastolic HF” and “systolic HF” frequently lead to the misunderstanding that HF can be divided into a condition in which there is diastolic dysfunction alone and a condition in which there is systolic dysfunction. To avoid any misunderstanding, HF with preserved EF or HF with reduced EF are currently used (14). RISK FACTORS FOR DIASTOLIC DYSFUNCTION Left ventricular hypertrophy is one of the most common myocardial alterations in ESKD patients, and it is frequently accompanied by myocardial fibrosis and diastolic dysfunction (15). The structural changes that occur in the heart in uremic cardiomyopathy include cardiac hypertrophy, myocardial fibrosis, and thickening of the intramural arteries and arterioles (16). These structural changes predispose the hearts of ESKD patients to diastolic dysfunction, mainly because of the fibrotic changes in the uremic heart caused by CKD-related risk factors. Cardiac hypertrophy and vascular remodeling may be adaptive responses to pressure and volume overload (15). The risk factors for LVH and cardiac fibrosis in ESKD patients are divided into three categories: afterload-related, preload-related, and neither afterload- nor preload-related. Preload-related risk factors consist of intravascular volume expansion, anemia, and high-flow arteriovenous fistulas created for vascular access in hemodialysis patients. The myocardial damage caused by these preload risk factors results in myocardial cell lengthening and eccentric © 2015 The Authors Therapeutic Apheresis and Dialysis © 2015 International Society for Apheresis
429
LV remodeling. Afterload-related risk factors include systemic arterial resistance and large-vessel compliance, which cause myocardial cell thickening and concentric LV remodeling (7). In association with hypertension, both serum transforming growth factor-β and procollagen type I levels have been found to be higher in hypertensive patients with LVH, when compared with controls without ventricular alterations (17). The serum inflammatory biomarker levels of CKD patients who developed LVH have been found to be significantly higher than in CKD patients without LVH (18). The same relationship has been noted in regard to serum C-reactive protein and N-terminal pro-B-type natriuretic peptide levels (19), suggesting a link between LV filling pressure and inflammation. CKD patients frequently have an activation of the renin-angiotensin-aldosterone system (RAAS), which can induce myocardial fibrosis and hypertrophy. Activation of the RAAS in heart tissue seems to be critically involved in the volume overload status observed in ESKD patients, but angiotensin II and aldosterone can also cause myocardial cell hypertrophy and interstitial fibrosis independent of afterload (7). Angiotensin II promotes the growth of both fibroblasts and cardiomyocytes, which contributes to the uremic cardiomyopathy of hemodialysis patients (20), and high plasma aldosterone levels have been found to be correlated with LVH in hemodialysis patients independent of hypertension (21). Anemia in ESKD patients has been found to be associated with LVH (22). The presence of anemia during the first year of renal replacement therapy has been found to be associated with an increase in the prevalence of LVH (23). Anemia plays a central role in the development of diastolic HF in dialysis patients. The impact of anemia on cardiomyopathy among ESKD patients was recently evaluated in a clinical study that included serial echocardiograms, and anemia was found to be an independent risk factor for diastolic HF even after adjustment for age, diabetes, and ischemic heart disease (24). Mineral metabolism disorders, including hyperphosphatemia and elevated parathyroid hormone levels, are common in ESKD patients and have been reported to be related to cardiovascular mortality in epidemiological studies (25). Exposure of vascular smooth muscle cells to high phosphate concentrations alters their phenotype to osteoblast-like cells and induces vascular calcification (26).Although there are several mechanisms by which hyperparathyroidism can induce LVH, including direct effects on myocytes and interstitial fibroblasts (27), a permissive role of parathyroid hormone (PTH) in interstitial fibrosis has
Ther Apher Dial, Vol. 19, No. 5, 2015
430
T Ogawa et al.
been demonstrated (28). Fibroblast growth factor-23 (FGF23) is a hormonal regulator of circulating phosphate and vitamin D levels (29). Serum FGF23 is elevated in ESKD patients and is a prognostic marker for a poor outcome in hemodialysis patients (30). FGF23 has been proposed to be associated with LVH in hemodialysis patients (31). Hypovitaminosis D is a common finding in CKD patients (32) and is associated with myocardiac hypertrophy (33), and it is related to early cardiovascular mortality and sudden cardiac death in hemodialysis patients (34,35). Although the vitamin D receptor (VDR) is found ubiquitously throughout the body, including in cardiovascular and immune cells, its classical action involves mineral metabolism (36). It has been well established that vitamin D has several biological effects on the heart, including a stimulating effect on cardiomyocyte contraction, proliferation, hypertrophy, differentiation, and collagen expression (37). Vitamin D may also play a role in the maintenance of vascular tone and cardiac output (38). However, a recent report has shown that 48-week therapy with paricalcitol did not alter left ventricular mass index (LVMi) or improve certain measures of diastolic dysfunction in patients with CKD (39).Thus, we should be careful to use active vitamin D for the treatment of diastolic dysfunction in ESKD patients. DIAGNOSIS OF DIASTOLIC DYSFUNCTION Diastolic dysfunction is difficult to diagnose, because there are no simple and reliable diagnostic criteria. Diastolic dysfunction can be diagnosed clinically when a patient exhibits the clinical symptoms and findings of HF but no decrease or only a minimal decrease in LVEF. Elevated LV filling pressure is the main physiological finding in diastolic HF and is associated with the onset of symptoms (40). LV filling pressure is primarily regulated by filling and by the passive properties of the LV wall, but it is also affected by alterations in myocardial relaxation and diastolic myocardial tone.Increased afterload can delay myocardial relaxation, particularly when combined with high preload, thereby contributing to filling pressure elevation (41). According to the European Society of Cardiology, a diagnosis of diastolic HF requires the presence of: (i) signs or symptoms of HF; (ii) normal or mildly abnormal systolic LV function (EF > 50%); and (iii) evidence of diastolic dysfunction (40). Ideally, gold standard measurements of diastolic function should be obtained invasively by cardiac catheterization. Filling pressure is considered elevated when mean pulmonary capillary wedge pressure is >12 mm Hg or Ther Apher Dial, Vol. 19, No. 5, 2015
when LV end-diastolic pressure is >16 mm Hg (42). However, for practical and ethical reasons, diastolic indices determined by cardiac catheterization cannot be directly applied in routine clinical practice. Noninvasive Doppler echocardiographic assessment of diastolic function becomes essential in practice, and every effort should be made to obtain reliable estimates of LV filling pressure. Doppler mitral flow velocities (early to late filling velocity; E/A ratio) have conventionally been used in clinical practice to assess diastolic function, however, they are strongly load-dependent (43), and may exhibit pseudonormalization of the LV filling pattern, such as a mitral flow pattern that appears to be normal despite the presence of chronic diastolic dysfunction (44). Alternative methods have been successfully used to overcome the limitations of Doppler mitral flow velocities, and they include measurement of pulmonary venous flow, tissue Doppler imaging of mitral annulus velocity, and the left atrium volume index (LAVi). The ratio of early mitral flow velocity (E) to early mitral annulus velocity (e′), called the E/e′ ratio, was the most reliable noninvasive predictor of elevated LV filling pressure in a study of renal transplant candidates (45). Similarly, left atrium enlargement, estimated on the basis of the LAVi, has been recognized as a surrogate marker for chronically augmented LV diastolic pressure in hemodialysis patients (46). In addition, LAVi >32 mL/m2 was found to be a predictor of death in a study with patients on chronic hemodialysis (47). As shown in Table 1, a recent guideline recommends a grading scheme for diastolic dysfunction that integrates information from multiple indices (42), and significantly predicts all-cause mortality in hemodialysis patients (48). Patients with grade I diastolic dysfunction (impaired relaxation) according to the scheme have a mitral E/A ratio
Therapeutic Apheresis and Dialysis 2015; 19(5):427–435 doi: 10.1111/1744-9987.12301 © 2015 The Authors Therapeutic Apheresis and Dialysis © 2015 International Society for Apheresis
Review
Left Ventricular Diastolic Dysfunction in End-Stage Kidney Disease: Pathogenesis, Diagnosis, and Treatment Tetsuya Ogawa, Misato Koeda, and Kosaku Nitta Department of Medicine, Medical Center East and Kidney Center, Tokyo Women’s Medical University, Tokyo, Japan
Abstract: Diastolic dysfunction is frequently observed in end-stage kidney disease (ESKD), and ESKD patients have many risk factors for heart failure (HF), including hypertension, diabetes, and coronary artery disease. Diastolic HF, also called HF with preserved ejection fraction, refers to a clinical syndrome in which patients have symptoms and signs of HF, normal or near normal left ventricular (LV) systolic function, and evidence of diastolic dysfunction manifested by abnormal LV filling and elevated filling pressure. Recent reports suggest that HF
with preserved ejection fraction is more common in hemodialysis patients than HF with low ejection fraction. Diastolic HF in ESKD patients is a strong predictor of death. In this article, we review the information available in the literature on the pathogenesis, diagnosis, and potential treatment strategies of diastolic dysfunction or diastolic HF based on evidence obtained in the general population that is potentially applicable to ESKD patients. Key Words: Dialysis, Diastolic dysfunction, Doppler echocardiography, End-stage kidney disease, Mortality.
In the general population, heart failure (HF) is frequently associated with impaired left ventricular (LV) function. However, as many as 30–40% of all patients with typical symptoms of congestive HF have a normal or slightly reduced LV ejection fraction (EF), and diastolic dysfunction has been implicated as a major contributor, if not the primary cause of the congestive HF in such patients (1). The syndrome of clinical HF with preserved LV systolic function in the absence of cardiac valvular lesions is often referred to as diastolic dysfunction with abnormal LV filling and elevated filling pressure. However, whether diastolic dysfunction is a cause of HF remains a matter of controversy. Diastolic dysfunction is typically observed in hypertensive patients and has a particularly high prevalence in the elderly population (2). Caruana et al. showed that 109 of 159 patients with suspected HF in the absence of LV systolic dysfunction were incorrectly
diagnosed with diastolic HF (3). While investigators may agree that some patients with HF have a normal EF, they doubt that the underlying mechanism is diastolic dysfunction. In some case series, the relations between LV pressure and volume measured by cardiac catheterization have not conformed to the classical pattern of diastolic dysfunction (4). Cardiovascular disease, including HF, is a major cause of death among patients with end-stage kidney disease (ESKD) in Japan (5). As risk factors for HF, i.e. volume expansion, hypertension, diabetes, dyslipidemia, and atherosclerosis are frequently present in patients with chronic kidney disease (CKD) (6). Subclinical diastolic dysfunction has recently been reported to be the most common echocardiographic finding in asymptomatic hemodialysis patients with LV hypertrophy (LVH) (7).The most common factors associated with diastolic dysfunction are aging, hypertension, diabetes, coronary artery disease, LVH and cardiomyopathy. These factors are often associated with the development of myocardial fibrosis and decreased ventricular compliance, which are pathophysiological features of diastolic HF. This article reviews the literature on the pathogenesis, diagnosis, and treatment of diastolic dysfunction or diastolic HF in ESKD patients, based on
Received September 2014; revised December 2014. Address correspondence and reprint requests to Dr Kosaku Nitta, Department of Medicine, Kidney Center, Tokyo Women’s Medical University, Tokyo 162-8666, Japan. Email: knitta@ kc.twmu.ac.jp
427
428
T Ogawa et al.
evidence obtained in the general population that is potentially applicable to CKD patients, including ESKD patients. PATHOGENESIS OF DIASTOLIC DYSFUNCTION The majority of patients with diastolic dysfunction exhibit abnormal active myocardial relaxation and passive ventricular stiffness that contribute to abnormal ventricular filling in diastole and shift the normal ventricular pressure-volume curve upward and to the left, thereby resulting in a higher LV filling pressure for any given filling volume (8). In addition, neurohormonally mediated increases in venous tone and systemic arterial pressure may contribute to shifting blood to the central circulation, and thereby further increase LV filling pressure. When LV diastolic function is impaired, cardiac output is reduced, because the LV is not filled enough in diastole due to LV inflow obstruction. By contrast, to compensate for reduced cardiac output, increasing the inflow pressure to the LV and consequently LV end-diastolic pressure becomes necessary, and that in turn increases left atrial pressure. As a result, LV dysfunction tends to cause pulmonary congestion (9). The end-systolic pressure-volume relationship in diastolic dysfunction is the same as in a normal heart,
but the end-diastolic pressure-volume relationship shifts upwards (Fig. 1a) (10), and LV end-diastolic pressure rises as a result. When an abrupt increase in blood pressure occurs, since the pressure-volume curve shifts to the upper right without any decrease in Emax (absolute index of contractibility), when an abrupt increase in blood pressure occurs, pulmonary congestion is induced by the significant increase in LV end-diastolic pressure (Fig. 1b). Left ventricular contractility appears to be considered normal in diastolic dysfunction; however, the contractile velocity in systole measured by tissue Doppler echocardiography is low in both systolic and diastolic dysfunction (11), and local contractility in the longitudinal direction is known to be impaired in diastolic HF (12). Recent findings suggest that contractility decreases even in diastolic HF at the myocardial level. In contrast, diastolic function is also impaired in systolic HF, and it has been shown to decrease exercise tolerance and to be one of the determinants of the outcome (13). Diastolic and systolic HF are not considered separate, independent entities, and the single syndrome hypothesis of HF shown in Figure 2 is advocated. In that hypothesis, HF is a single continuous disease spectrum and systolic and diastolic HF are phenotypes at two extremes. HF with LVEF of 45 to 50% would be located in the middle of the continuum of the disease spectrum.
FIG. 1. (a) The end-diastolic pressure-volume curve shifts upwards in diastolic heart failure, followed by a rise in left ventricular (LV) end-diastolic pressure. (b) When an abrupt increase in blood pressure occurs, the pressure-volume curve shifts to the upper right without any decrease in Emax in patients with diastolic dysfunction.
Ther Apher Dial, Vol. 19, No. 5, 2015
© 2015 The Authors Therapeutic Apheresis and Dialysis © 2015 International Society for Apheresis
Diastolic Dysfunction in ESKD
FIG. 2. Diastolic and systolic heart failure are not considered separate, independent entities.
By contrast, some investigators have reported that diastolic dysfunction should be widely recognized as a determinant of the pathophysiology in HF (14). LV systolic dysfunction occurs in some patients with diastolic HF. The terms “diastolic HF” and “systolic HF” frequently lead to the misunderstanding that HF can be divided into a condition in which there is diastolic dysfunction alone and a condition in which there is systolic dysfunction. To avoid any misunderstanding, HF with preserved EF or HF with reduced EF are currently used (14). RISK FACTORS FOR DIASTOLIC DYSFUNCTION Left ventricular hypertrophy is one of the most common myocardial alterations in ESKD patients, and it is frequently accompanied by myocardial fibrosis and diastolic dysfunction (15). The structural changes that occur in the heart in uremic cardiomyopathy include cardiac hypertrophy, myocardial fibrosis, and thickening of the intramural arteries and arterioles (16). These structural changes predispose the hearts of ESKD patients to diastolic dysfunction, mainly because of the fibrotic changes in the uremic heart caused by CKD-related risk factors. Cardiac hypertrophy and vascular remodeling may be adaptive responses to pressure and volume overload (15). The risk factors for LVH and cardiac fibrosis in ESKD patients are divided into three categories: afterload-related, preload-related, and neither afterload- nor preload-related. Preload-related risk factors consist of intravascular volume expansion, anemia, and high-flow arteriovenous fistulas created for vascular access in hemodialysis patients. The myocardial damage caused by these preload risk factors results in myocardial cell lengthening and eccentric © 2015 The Authors Therapeutic Apheresis and Dialysis © 2015 International Society for Apheresis
429
LV remodeling. Afterload-related risk factors include systemic arterial resistance and large-vessel compliance, which cause myocardial cell thickening and concentric LV remodeling (7). In association with hypertension, both serum transforming growth factor-β and procollagen type I levels have been found to be higher in hypertensive patients with LVH, when compared with controls without ventricular alterations (17). The serum inflammatory biomarker levels of CKD patients who developed LVH have been found to be significantly higher than in CKD patients without LVH (18). The same relationship has been noted in regard to serum C-reactive protein and N-terminal pro-B-type natriuretic peptide levels (19), suggesting a link between LV filling pressure and inflammation. CKD patients frequently have an activation of the renin-angiotensin-aldosterone system (RAAS), which can induce myocardial fibrosis and hypertrophy. Activation of the RAAS in heart tissue seems to be critically involved in the volume overload status observed in ESKD patients, but angiotensin II and aldosterone can also cause myocardial cell hypertrophy and interstitial fibrosis independent of afterload (7). Angiotensin II promotes the growth of both fibroblasts and cardiomyocytes, which contributes to the uremic cardiomyopathy of hemodialysis patients (20), and high plasma aldosterone levels have been found to be correlated with LVH in hemodialysis patients independent of hypertension (21). Anemia in ESKD patients has been found to be associated with LVH (22). The presence of anemia during the first year of renal replacement therapy has been found to be associated with an increase in the prevalence of LVH (23). Anemia plays a central role in the development of diastolic HF in dialysis patients. The impact of anemia on cardiomyopathy among ESKD patients was recently evaluated in a clinical study that included serial echocardiograms, and anemia was found to be an independent risk factor for diastolic HF even after adjustment for age, diabetes, and ischemic heart disease (24). Mineral metabolism disorders, including hyperphosphatemia and elevated parathyroid hormone levels, are common in ESKD patients and have been reported to be related to cardiovascular mortality in epidemiological studies (25). Exposure of vascular smooth muscle cells to high phosphate concentrations alters their phenotype to osteoblast-like cells and induces vascular calcification (26).Although there are several mechanisms by which hyperparathyroidism can induce LVH, including direct effects on myocytes and interstitial fibroblasts (27), a permissive role of parathyroid hormone (PTH) in interstitial fibrosis has
Ther Apher Dial, Vol. 19, No. 5, 2015
430
T Ogawa et al.
been demonstrated (28). Fibroblast growth factor-23 (FGF23) is a hormonal regulator of circulating phosphate and vitamin D levels (29). Serum FGF23 is elevated in ESKD patients and is a prognostic marker for a poor outcome in hemodialysis patients (30). FGF23 has been proposed to be associated with LVH in hemodialysis patients (31). Hypovitaminosis D is a common finding in CKD patients (32) and is associated with myocardiac hypertrophy (33), and it is related to early cardiovascular mortality and sudden cardiac death in hemodialysis patients (34,35). Although the vitamin D receptor (VDR) is found ubiquitously throughout the body, including in cardiovascular and immune cells, its classical action involves mineral metabolism (36). It has been well established that vitamin D has several biological effects on the heart, including a stimulating effect on cardiomyocyte contraction, proliferation, hypertrophy, differentiation, and collagen expression (37). Vitamin D may also play a role in the maintenance of vascular tone and cardiac output (38). However, a recent report has shown that 48-week therapy with paricalcitol did not alter left ventricular mass index (LVMi) or improve certain measures of diastolic dysfunction in patients with CKD (39).Thus, we should be careful to use active vitamin D for the treatment of diastolic dysfunction in ESKD patients. DIAGNOSIS OF DIASTOLIC DYSFUNCTION Diastolic dysfunction is difficult to diagnose, because there are no simple and reliable diagnostic criteria. Diastolic dysfunction can be diagnosed clinically when a patient exhibits the clinical symptoms and findings of HF but no decrease or only a minimal decrease in LVEF. Elevated LV filling pressure is the main physiological finding in diastolic HF and is associated with the onset of symptoms (40). LV filling pressure is primarily regulated by filling and by the passive properties of the LV wall, but it is also affected by alterations in myocardial relaxation and diastolic myocardial tone.Increased afterload can delay myocardial relaxation, particularly when combined with high preload, thereby contributing to filling pressure elevation (41). According to the European Society of Cardiology, a diagnosis of diastolic HF requires the presence of: (i) signs or symptoms of HF; (ii) normal or mildly abnormal systolic LV function (EF > 50%); and (iii) evidence of diastolic dysfunction (40). Ideally, gold standard measurements of diastolic function should be obtained invasively by cardiac catheterization. Filling pressure is considered elevated when mean pulmonary capillary wedge pressure is >12 mm Hg or Ther Apher Dial, Vol. 19, No. 5, 2015
when LV end-diastolic pressure is >16 mm Hg (42). However, for practical and ethical reasons, diastolic indices determined by cardiac catheterization cannot be directly applied in routine clinical practice. Noninvasive Doppler echocardiographic assessment of diastolic function becomes essential in practice, and every effort should be made to obtain reliable estimates of LV filling pressure. Doppler mitral flow velocities (early to late filling velocity; E/A ratio) have conventionally been used in clinical practice to assess diastolic function, however, they are strongly load-dependent (43), and may exhibit pseudonormalization of the LV filling pattern, such as a mitral flow pattern that appears to be normal despite the presence of chronic diastolic dysfunction (44). Alternative methods have been successfully used to overcome the limitations of Doppler mitral flow velocities, and they include measurement of pulmonary venous flow, tissue Doppler imaging of mitral annulus velocity, and the left atrium volume index (LAVi). The ratio of early mitral flow velocity (E) to early mitral annulus velocity (e′), called the E/e′ ratio, was the most reliable noninvasive predictor of elevated LV filling pressure in a study of renal transplant candidates (45). Similarly, left atrium enlargement, estimated on the basis of the LAVi, has been recognized as a surrogate marker for chronically augmented LV diastolic pressure in hemodialysis patients (46). In addition, LAVi >32 mL/m2 was found to be a predictor of death in a study with patients on chronic hemodialysis (47). As shown in Table 1, a recent guideline recommends a grading scheme for diastolic dysfunction that integrates information from multiple indices (42), and significantly predicts all-cause mortality in hemodialysis patients (48). Patients with grade I diastolic dysfunction (impaired relaxation) according to the scheme have a mitral E/A ratio
