The Clinical Epidemiology of Cardiac Disease in Chronic Renal Failure

The annual mortality from cardiovascular disease in dialysis patients is substantially higher than in the general population (Figure 1) (1). The 5-yr survival of men >64 yr old starting dialysis is worse than that of men with colon cancer and prostate cancer (2). The 5-yr survival of women >64 yr old starting dialysis is worse than that of women with breast cancer and colon cancer (2). About half the deaths in dialysis patients are attributed to cardiovascular disease (2). Hospitalizations of dialysis patients occur frequently and about one-third are the result of cardiovascular disease (2). Despite enormous morbidity and premature mortality resulting from cardiovascular disease, it is only recently that the clinical epidemiology of cardiovascular disease in chronic renal failure has become a major focus of nephrology research.Figure 1: Cardiovascular disease mortality by age, race, and gender in the general population and in dialysis patients. Cardiovascular mortality is defined as death due to arrhythmias, cardiomyopathy, cardiac arrest, myocardial infarction, atherosclerotic heart disease, and pulmonary edema. Data from the general population are from the National Center for Health Statistics multiple cause of mortality files 1993. Data from dialysis patients include hemodialysis and peritoneal dialysis combined from USRDS 1994-1996. Reprinted with permission from Am J Kidney Dis 32Suppl 3: S115, 1998.A task force convened by the National Kidney Foundation has considered whether strategies for prevention and treatment of cardiovascular disease in the general population are applicable in patients with chronic renal disease. Two target conditions (coronary artery disease and left ventricular hypertrophy) and four target populations (chronic renal insufficiency, hemodialysis, peritoneal dialysis, and renal transplantation) were considered. Detailed reports are available in a supplement of the American Journal of Kidney Diseases (3). The major focus was on traditional cardiac risk factors identified in the general population, including hyperlipidemia, hypertension, diabetes mellitus, tobacco use, menopause, and physical inactivity. In addition, a recent volume of Seminars in Dialysis was devoted to consideration of potential uremia-related risk factors (4). These included risk factors altered by the uremic state, such as dyslipidemia, prothrombotic factors, hyperhomocysteinemia, and also risk factors characteristic of chronic uremia, such as hemodynamic overload, anemia, increased oxidant stress, hypoalbuminemia, and divalent ion abnormalities (Table 1).Table 1: Cardiac risk factors in chronic uremiaPathogenesis of Cardiac Disease Manifestations of ischemic heart disease, such as angina pectoris or myocardial infarction, are caused by disorders of coronary vessel perfusion. Ischemic heart disease is usually the result of critical coronary artery disease, but in 27% of hemodialysis patients ischemic symptoms are caused by nonatherosclerotic disease (5) (Figure 2). The latter is associated with the underlying cardiomyopathy, small vessel disease (caused by hypertension, diabetes mellitus, and calcium phosphate deposition), reduced capillary density, and abnormal myocyte bioenergetics (6). Left ventricular (LV) hypertrophy predisposes to ischemic symptoms by reducing coronary reserve.Figure 2: Cardiomyopathy and ischemic heart disease in chronic uremia.Heart failure is the most common symptom of an underlying cardiomyopathy (Figure 2). LV structure and function alters as a result of LV pressure and volume overload, and of myocyte death (6) (Figure 3). LV pressure overload results from hypertension, arteriosclerosis, and occasionally aortic stenosis. It causes concentric LV hypertrophy, with increased myocyte thickness and little change in LV volume. LV volume overload results from salt and water overload, anemia, and the arteriovenous fistula. It causes eccentric LV hypertrophy, with increase in myocyte length and increase in LV volume. Initially, the LV hypertrophy is adaptive in both types of overload, and is beneficial because energy is spared by maintaining stable wall stress. However, the LV hypertrophy eventually becomes maladaptive, and is harmful because of myocyte death (resulting from continuing LV overload), decrease in capillary density, increase in myocardial fibrosis, diastolic dysfunction, and LV conduction abnormalities. The LV volume-LV pressure curve is displaced to the left, and altered in such a manner that small changes in LV volume result in large changes in LV pressure, predisposing to symptomatic LV failure (6).Figure 3: Left ventricular (LV) pressure overload, LV volume overload, and myocyte death in chronic uremia.Myocyte death induces LV dilation with compensatory LV hypertrophy. Eventually, systolic dysfunction occurs. In addition to continuing LV overload, myocyte death may be caused by decreased large and small coronary vessel perfusion, hyperparathyroidism, malnutrition, and other factors associated with severe uremia (6) (Figure 3). Blood flow overload causes not only LV remodeling but also vascular remodeling. The latter results in arteriosclerosis with thickened, dilated, and noncompliant arteries (6). This is different from atherosclerosis, which is characterized by arterial plaques that are focal, intermittent in distribution, occlusive in nature, and with a predilection for arterial bifurcations. Arteriosclerosis predisposes to LV hypertrophy by diminishing arterial distensibility, and by enhancing arterial wave reflections, thus increasing the pulsatile work of the heart. There is a strong correlation between carotid artery intima-medial thickness and LV mass index (7). Arteriosclerosis also predisposes to ischemic heart disease by decreasing subendocardial coronary perfusion (6). Patients with chronic uremia have multiple risk factors predisposing to disorders of coronary perfusion and to atherosclerosis. They also have multiple risk factors predisposing to abnormalities of LV structure and function and to arteriosclerosis. Disorders of coronary perfusion predispose to cardiomyopathy and vice versa. The presence of symptomatic ischemic heart disease and the presence of heart failure on starting dialysis predict earlier death. However, the impact of ischemic heart disease is not independent of that of heart failure, suggesting that the final cardiac pathway to death is via LV dysfunction (8). Diagnosis The gold standard for diagnosis of coronary artery disease is coronary angiography. Most of the noninvasive tests for coronary disease are not sensitive in dialysis patients, although dobutamine echocardiography may be (9). Recently, combined dipyridamole-exercise thallium imaging was shown to be an accurate method for detecting coronary artery disease and for predicting future coronary events (10). It is usually not possible to use coronary arteriography in longitudinal studies and clinical trials of dialysis patients. Therefore, symptomatic ischemic heart disease has been the usual marker for coronary artery disease in longitudinal studies (8). M-mode echocardiography is an accurate diagnostic test for the diagnosis of concentric LV hypertrophy, LV dilation, and systolic dysfunction (11). LV mass index and LV volume index can be calculated. However, LV volume fluctuates in hemodialysis patients (12). Therefore, it is necessary to perform echocardiography at the patient's dry weight, preferably the day after dialysis. There is substantial variability over time in measurements of LV mass index and LV volume index. Nonetheless, it is a useful test for use in longitudinal studies and clinical trials (11). The diagnosis of LV failure is not difficult—dyspnea with signs of heart failure on clinical examination (bilateral basal crepitations and raised jugular venous pressure) and/or on chest x-ray (interstitial edema, pulmonary vascular redistribution) (13). The interpretation of these clinical signs is more problematic—Are they the result of salt and water overload or of primary heart disease? It may not be critical (or possible) to answer this question in most studies, because the presence of clinical heart failure on starting dialysis, regardless of whether it is caused by salt and water overload or of primary heart disease, is a very strong independent predictor of mortality. Chronic Renal Insufficiency Prevalence The prevalence of coronary artery disease in the general population is 5 to 12%, of LV hypertrophy 20%, and of heart failure 5% (1). In patients with chronic renal insufficiency, there are no data on coronary disease or heart failure (14). The prevalence of LV hypertrophy varies according to GFR: 27% in those with GFR ≥50 ml/min, 31% in those with GFR 25 to 49 ml/min, and 45% in those with GFR 20% above baseline or >20 g/m2 in 25% of the group (17). Risk Factors In one cross-sectional study, lower GFR, higher systolic BP, and lower hemoglobin level were associated with LV hypertrophy (15). In a cross-sectional study of 32 children with chronic renal failure, higher BP and higher serum creatinine were associated with higher LV mass (16). In the Canadian longitudinal study, increase in LV mass index, 12 mo after enrollment in the study, was associated with anemia, hypertension, and lower baseline LV mass index. The odds ratio was 1.32 for each 5 g/L fall in hemoglobin (P = 0.004) and 1.11 for each 5 mmHg rise in systolic BP (P = 0.01) (17). Patients Starting Dialysis Prevalence The prevalence of ischemic heart disease on starting dialysis, as reported by the national registries, was 41% in the United States, 36% in Australia and New Zealand, and 28% in Canada (14,15,16,17,18). In the United States, the prevalence of heart failure on starting dialysis was 40% (18). A Canadian multicenter longitudinal study followed 822 patients in 11 centers from the day of starting dialysis in 1993-1994 (19). A detailed evaluation of comorbidity was performed at that time. Eighty percent of the patients were Caucasian and 29% were diabetic. The prevalence of angina pectoris was 21%, of myocardial infarction 18%, of heart failure 35%, and of peripheral vascular disease 16%. Another Canadian study followed 432 patients who survived at least 6 mo on dialysis. Enrollment occurred from 1983-1991. Echocardiography at baseline revealed concentric LV hypertrophy in 42%, eccentric LV hypertrophy in 23%, isolated LV dilation in 4%, and systolic dysfunction in 16% (11). Only 16% had a normal echocardiogram (Figure 4). In this cohort, the prevalence of heart failure on starting dialysis was 31% and the prevalence of ischemic heart disease on starting dialysis was 22% (Figure 4).Figure 4: The prevalence and incidence of cardiac disease in a cohort of 432 Canadian dialysis patients followed from the start of dialysis for a mean of 41 mo (8 , 11 , 13). Consecutive patients were enrolled and followed if they survived 6 mo on end-stage renal disease (ESRD) therapy. prevalence = disease present at start of ESRD therapy. incidence = de novo disease developed during follow-up on dialysis therapy. = heart failure present at start of and during = heart failure present at start of but not de novo = disease not present at start of but occurred during follow-up on dialysis therapy. = disease not present at start of and occurred during Factors The prevalence of cardiovascular disease on starting dialysis that the of chronic renal disease is a of cardiac of this risk can be attributed to the of diabetes and in the of end-stage renal disease In the United in of from diabetes and from (2). is associated with more severe and coronary artery disease than that in patients LV mass index is higher in patients than in patients LV hypertrophy is associated with more in patients than in patients, or patients starting dialysis in the Canadian study, patients = had more concentric LV hypertrophy = symptomatic ischemic heart disease 18%, = and cardiac failure compared to patients = The presence of concentric LV hypertrophy, LV dilation, or systolic dysfunction on starting dialysis was associated with about a increase in the risk of heart failure, independent of age, and ischemic heart disease (11). The survival of patients with systolic dysfunction on starting dialysis was mo (Figure with an odds ratio for compared to those with normal of of age, and ischemic heart (11). The mortality yr of for both concentric LV hypertrophy and LV dilation was worse than for those with a normal echocardiogram (Figure percent survival in patients with systolic dysfunction, concentric LV hypertrophy, LV dilation, and normal echocardiogram on starting dialysis (11). Reprinted with permission from presence of heart failure on starting dialysis was associated with a increased risk of independent of age, and ischemic heart disease (Figure The presence of symptomatic ischemic heart disease was associated with a increased risk of independent of age and However, cardiac failure was included in the ischemic heart disease was no an independent predictor of death percent survival in patients with and heart failure on starting dialysis (13). Reprinted with permission from Kidney Prevalence and in the in a prevalence of for LV dilation diastolic and for systolic dysfunction 10 yr of hemodialysis, the prevalence of LV hypertrophy was and the prevalence of was The prevalence of heart failure in the United has increased from in to in the the prevalence of ischemic heart disease increased from to and Incidence LV dilation with compensatory hypertrophy after starting dialysis. A of dialysis patients from the Canadian study had four annual from the start of dialysis LV volume index was at baseline mo after start of increased by at mo from start of dialysis, by a 5 at and by at mo follow-up from start of dialysis. LV mass index at baseline was increased by g/m2 on first by g/m2 on and increased by g/m2 on The Canadian Study reported an per of myocardial infarction or angina in a cohort followed from the start of hemodialysis The of pulmonary or was per The incidence of de novo ischemic heart disease in Canadian cohort of dialysis patients ischemic heart disease on starting dialysis was during a follow-up of 41 an annual incidence of (Figure 4). The incidence of de novo heart failure was in the patients who not have heart failure on starting dialysis, an annual incidence of per (Figure 4). In the United States, the annual cardiovascular disease mortality in the general population is in hemodialysis patients it is at (Figure This very substantially increased mortality occurred in and patients (Figure The incidence of death due to ischemic heart disease varies according to have a lower incidence of coronary artery disease than in the general population. This the dialysis population the annual death for ischemic heart disease for hemodialysis patients to yr per patient years were in and 32 in the United for were and Patients on dialysis who present with myocardial infarction have mortality from cardiac causes and survival In patients on dialysis, mortality after myocardial infarction was at at and at 5 patients and patients had higher of mortality. These data are with the that a decrease in coronary perfusion in patients with overload cardiomyopathy be The survival the of de novo heart failure during the of dialysis was mo (13). Dialysis of between patients with peritoneal dialysis and hemodialysis is with because of in the of ESRD in Canada comorbidity that present on starting dialysis, are substantially higher in hemodialysis than in peritoneal dialysis patients The hemodynamic of hemodialysis the of LV dilation and compensatory LV hypertrophy, in peritoneal dialysis patients the of a anemia, and volume not In patients with peritoneal dialysis, LV volume decreased by 5 during the first of follow-up from start of dialysis. In patients on hemodialysis, LV volume increased by and LV mass index increased by g/m2 during the first of follow-up In the group of patients only with peritoneal dialysis, developed de novo heart failure of those with hemodialysis (P = In this study, hemodialysis had a survival over peritoneal dialysis because of the impact of in the latter serum in peritoneal dialysis patients in the first yr of for of the increase in mortality It that the to cardiac death is different for hemodialysis and peritoneal dialysis patients. In peritoneal dialysis patients on treatment for a prevalence of left dilation and LV hypertrophy was the latter the result of The prevalence of LV hypertrophy was lower in those during the first to yr of treatment and higher in those for 5 yr In the United States, the prevalence of ischemic heart disease in peritoneal dialysis patients was about as was that of heart failure (18). The cardiovascular disease annual mortality is to that in hemodialysis patients (1). The risk of death from myocardial infarction was higher in peritoneal hemodialysis patients in The death from myocardial infarction was per 100 patient years in peritoneal dialysis patients per 100 patient years in hemodialysis patients Risk Factors for Cardiac Disease in Dialysis Patients The most to risk factors for cardiac disease in dialysis patients patients the disease of on starting the potential risk and patients de novo disease There are few such longitudinal studies Cardiomyopathy A control with follow-up identified systolic BP as a risk for the of LV hypertrophy cardiac identified by serial echocardiography from the start of dialysis was associated with hemodialysis with peritoneal and fall in hemoglobin from the was associated with a 10 g/m2 rise in LV mass index. These data are with the that systolic causes concentric hypertrophy, and that and hemodynamic overload cause an increase in LV with compensatory hypertrophy. patients with LV dilation were compared to those with normal independent with the of LV dilation included ischemic heart disease, anemia, hypertension, and (11). risk factors for the of de novo heart failure in dialysis patients are shown in (13). uremia-related risk factors for de novo heart failure include anemia, hypertension, and 2: risk factors for the of de novo heart failure in dialysis patients Disease risk factors for the of de novo ischemic heart disease in dialysis patients are shown in (8). risk factors for de novo ischemic disease include the underlying cardiomyopathy, hypertension, hypoalbuminemia, but not 3: risk factors for the of de novo ischemic heart disease in dialysis patients is not due to increased peripheral but may increased cardiac from anemia, salt and water overload, or arteriovenous or it may arteriosclerosis. is a risk for LV hypertrophy, LV dilation, heart failure, and ischemic heart disease, but is a risk for mortality (Table 4). The has been in multiple It is by the that BP is a marker for cardiac disease death. This interpretation is by the A of dialysis patients have cardiac disease on starting dialysis. In patients who cardiac failure on dialysis, the time to this is than the follow-up after the BP after the of heart percent of deaths are by cardiac failure 4: between pressure of a rise in mean arterial pressure level of 10 and and clinical in dialysis patients It is one as a cardiac risk for cardiac failure and ischemic heart disease, because it may be a marker for malnutrition, dialysis, an associated prothrombotic state, dyslipidemia, chronic or of which be to the heart In the of of with in the and more recently with induces LV dilation and compensatory LV hypertrophy, and is a risk for de novo heart failure and earlier death studies of of with have but not of LV mass and volume for age and dialysis patients had of of disorders and of de novo heart failure, but higher of de novo ischemic heart disease, and cardiovascular mortality than dialysis patients (Table The cardiac morbidity and mortality of patients to be via ischemic disease, than of cardiomyopathy, on dialysis of to dialysis patients The prevalence of in chronic renal disease is higher than in the general population, but varies on the of target population, cause of renal disease, and level of renal function The prevalence of increased or is in patients with chronic renal insufficiency and patients by peritoneal dialysis, and renal to target populations have a prevalence of increased usually with a to in chronic uremia is by the impact of malnutrition, which serum Chronic uremia is associated with higher and altered which are A longitudinal study has that a level is a risk for future cardiac events In patients were followed from the start of dialysis. patients from myocardial infarction had higher than and higher and There are no longitudinal studies reported for large of patients followed from the start of dialysis, which the of cardiac risk associated with the abnormalities in chronic Risk Factors uremia-related cardiac risk factors include salt and water overload, flow dialysis, hyperhomocysteinemia, increased oxidant stress, increased prothrombotic factors, divalent ion hyperparathyroidism, and insufficiency (4). However, there are no longitudinal studies with an and large of patients that have the of cardiac risk associated with each of these potential risk Risk The level of to the of an is from clinical A small clinical has that the of LV hypertrophy A Canadian multicenter study of patients compared the of of with on LV structure in hemodialysis patients with concentric LV hypertrophy or LV dilation of to of concentric LV hypertrophy or LV dilation, but it to LV dilation in patients with normal LV In the latter there was a strong correlation between change in LV volume and change in hemoglobin level at 12 mo after the start of the of to in clinical have been The the of of with compared with in patients with symptomatic cardiac disease, who were hemodialysis A of hemodialysis patients with symptomatic heart failure or ischemic heart disease was The primary was death or first myocardial The was because of deaths (Figure and increased vascular in the group to of These with the Canadian that it is to and in the of cardiac disease, by the time at which LV dilation has developed or clinical symptoms from or heart failure have to hemoglobin in the or on starting dialysis can of cardiac disease is percent survival in hemodialysis patients with cardiac disease, to of compared to of with There were deaths and first myocardial = in the normal group = deaths and myocardial = in the group a of = (P = Reprinted with permission from J study in the United States, a of dialysis to a be the between of dialysis, hypoalbuminemia, and cardiac the target of and whether of the target of dialysis can cardiac In the of trials in chronic uremia, it to strategies for prevention and treatment of cardiovascular disease in the general population to patients with chronic uremia (1). These The of the National for and of BP, which the and target BP for to the risk of cardiovascular disease The of the National for treatment and target for or that patients with chronic renal disease are at risk of cardiac disease. of to the risk of cardiovascular disease in patients with coronary artery disease or in those who are at risk of coronary disease. of level of physical for per day for most of the Renal Patients who renal are a of the dialysis population in that they are and have little cardiac In the Canadian study, only of the of dialysis patients who were had heart failure and had myocardial infarction Nonetheless, of had abnormal LV structure and/or function LV mass index in those with concentric LV hypertrophy. LV mass index and LV volume in those with LV However, in patients LV structure not It was that 12 patients with systolic dysfunction Renal is a of chronic renal insufficiency and thus a of cardiac The prevalence of LV hypertrophy is between and (14). The incidence of myocardial infarction is to 5 that of the general population patients a A prevalence of coronary artery disease, has been in The risk of vascular events was higher in those with coronary disease compared to those reported on the incidence of ischemic heart disease in renal for mo from to Twelve percent developed major ischemic heart disease, and the incidence was percent of deaths were due to ischemic heart disease. These with the that this population has an annual cardiovascular mortality of and cause of death was attributed to cardiac disease in of that cardiac disease is a major This increase in because there has been a substantial in during the and a substantial in the of renal The clinical epidemiology of cardiac disease in chronic renal disease has become a major of during the The Renal Data work on the epidemiology of cardiac disease in the population of dialysis patients has on the of disease. The of cardiovascular disease in chronic uremia has been by and in The of LV disorders in the of cardiac symptoms and of risk factors for cardiac disease has been by the Canadian longitudinal Nonetheless, there is a in the clinical epidemiology of cardiac disease in chronic renal insufficiency, peritoneal dialysis, and renal the clinical of uremia-related risk and the clinical of risk as by in these is with of because the potential for and of in patients with chronic renal disease is