Anemia and Cardiac Risk
Hypertension is well recognized for its role not only as an etiologic factor for cardiovascular diseases, such as myocardial infarction and angina, but also for its ability to aggravate the course of many established cardiovascular diseases. Early diagnosis and aggressive treatment of hypertension at any point has become a critical component in the prevention and management of cardiac disease. Anemia, which is often untreated or inadequately treated, is emerging as another potentially common contributor to the development and progression of cardiovascular disease (CVD).¹ Although the complete picture of anemia’s role in CVD is currently unknown, hemodynamic changes brought about by this condition have cardiovascular consequences that could both predispose toward and aggravate existing cardiac disease.

Anemia and Cardiac Pathophysiology
Anemia provokes a series of cardiovascular alterations that may result in a compensatory increase in cardiac output and blood flow in the short term. These initially favorable adaptations, however, may lead to cardiac structural changes, which could predispose to CVD over time.^2,3 For patients with known CVD, anemia may be particularly problematic. It is well established that anemia has adverse effects on myocardial oxygenation that result in the provocation or acceleration of angina, and anemia may worsen congestive heart failure (CHF).⁴

Inadequate tissue oxygenation resulting from anemia appears to be the initial trigger for a number of specific hemodynamic adjustments.^5,6 Systemic arterial dilatation leads to decreased systemic vascular resistance and reduced afterload, which may improve stroke volume.⁷ Anemia decreases blood viscosity, which may improve venous return and thus augment preload. Anemia also activates the sympathetic nervous system, which induces an increase in heart rate.⁸ These changes in the heart and circulation act to raise cardiac output in the short term.

In contrast, over the long term, adaptations that initially increase cardiac output may lead to left ventricular enlargement and left ventricular hypertrophy (LVH). These two forms of cardiac remodeling predispose to heart failure and may aggravate coronary artery disease. The sustained sympathetic activation that accompanies anemia may be particularly problematic when accompanied by ventricular enlargement and LVH. Sympathetic activation is now recognized to play a major role in the pathophysiology of heart failure and beta blockade has emerged as a major form of therapy for this syndrome.^9,10

Chronic anemia may have adverse effects on the vasculature as well. Arterial hypertrophy and remodeling may occur as a result of sustained increases in cardiac output. This may reverse the early vasodilation characteristic of anemia and lead to increased systemic vascular resistance, which further contributes to the development of LVH and poor cardiac function. Early on these changes may be reversible; however, in conditions such as chronic kidney disease (CKD), they may become permanent.⁵

Anemia and Cardiac Morbidity and Mortality
The adverse cardiovascular effects of anemia in (CKD) have been well established. New data are now emerging to suggest this condition may represent an important treatable cause of cardiac morbidity and mortality in patients with heart failure as well. Anemia also appears to contribute to the development of cardiac symptoms in cancer patients.

CKD
The relationship between anemia and CVD has been well established in patients with CKD. Two studies in patients with predialysis CKD, conducted by Levin and colleagues, demonstrated that anemia is an independent risk factor for the development of LVH. Specifically, decreasing Hb was associated with increasing risk of LVH. The first study showed a 6% increase in the risk of LVH for each 1 g/dL decrease in Hb.¹¹ The second, larger study showed an even greater risk: an increase of 32% in LVH risk for each 0.5-g/dL decrease in Hb (P = 0.004).² This study identified three risk factors that contributed to the development of LVH in patients with CKD: Hb concentration, systolic blood pressure, and baseline left ventricular mass index. Similarly, in patients with end-stage renal disease (ESRD) undergoing dialysis, left ventricular end-diastolic volume and left ventricular mass both were found to increase with decreasing Hb levels.¹² Decreasing Hb levels have also been associated with a greater risk of the development of de novo or recurrent heart failure and increased mortality in this population.³

Collins and colleagues, in their study of nearly 67,000 ESRD patients starting dialysis, demonstrated that lower Hct is associated with higher cardiac-related hospitalizations and mortality at 1 year.¹³ Patients with Hct <30% or 30% to <33% were found to have a significantly higher risk of cardiac death than patients with Hct =33% to <36% at 1 year [RR 1.74 (95% CI, 1.66-1.83) and RR 1.25 (95% CI, 1.20-1.30), respectively]. The risk of cardiac- related hospitalization was also significantly higher in patients with Hct <30% or 30% to <33% than in those with Hct =33% to <36% [RR 1.3 (95% CI, 1.21- 1.38) and RR 1.17 (95% CI, 1.11-1.18), respectively]. Interestingly, those with Hct =36% to <39% had even lower cardiac- hospitalization risk than did those in the benchmark =33% to <36% Hct group (RR, 0.75; 95% CI, 0.71-0.82).

CHF In the last two decades, CHF has become a serious public health problem in western industrialized countries, and its prevalence continues to increase throughout the world. An estimated 5 million patients currently suffer from this condition in the United States, with approximately 400,000 new cases reported annually.^14-16 Despite treatment advances, CHF is associated with a high rate of morbidity and mortality.^17-19

The incidence and prevalence of anemia in CHF patients cannot be precisely determined from existing data, but retrospective studies suggest that reduced Hb is common in this syndrome. Patients hospitalized with CHF have been reported to have a mean Hb level of approximately 12 g/dL, and it has been demonstrated that the Hb level decreases as the severity of heart failure progresses.^16,17 For example, a retrospective analysis of 142 patients with CHF revealed that the prevalence of a Hb level <12 g/dL increased with the severity of the disease, reaching a prevalence of 79.1% in patients with New York Heart Association (NYHA) functional classification IV.²⁰ In addition, endogenous erythropoietin levels have been shown to increase with increasing severity of CHF.^16,18,19

Several potential mechanisms have been proposed to explain the relationship between anemia and CHF. Heart failure is often complicated by impaired renal function, which may result in decreased production of endogenous erythropoietin. Some evidence suggests that low cardiac output, especially likely in severe CHF, may impair bone marrow function.²¹ For example, a recent report using a mouse model demonstrated a 40% to 50% reduction in progenitor cells in the bone marrow of animals with infarcts, which appeared to be due to apoptosis, possibly induced by cytokines.²²

Another potential mechanism is rightsided heart failure with passive congestion, which may cause sufficient malabsorption and nutritional deficits to result in reduced Hb.²³ The use of angiotensinconverting enzyme inhibitors, while important in heart failure management, may inhibit the synthesis of endogenous erythropoietin.²⁴ Additionally, a systemic inflammatory state with activation of cytokines is increasingly recognized as an important part of the maladaptive neurohormonal activation that occurs in CHF. Cytokines and other mediators of this systemic inflammatory response may be involved in the development and progression of anemia. Finally, the increased levels of unbound iron seen in anemia can theoretically catalyze the peroxidation of lipids, thus enhancing oxidative stress and proinflammatory responses and potentially aggravating anemia.²⁵

Epidemiological data from several large heart failure clinical trials have demonstrated an association between anemia and adverse outcomes in this syndrome. Lower Hct and Hb values in patients with CHF have been associated with increased mortality risk. A recent retrospective analysis of the Studies of Left Ventricular Dysfunction (SOLVD) trial showed that in several thousand patients, reduced Hct was an independent risk factor for mortality.²⁶ A retrospective cross-sectional analysis of 1,734 patients with advanced CHF, referred to UCLA Medical Center between 1983 and 1999, confirmed an inverse correlation between Hb level and mortality. In addition, a lower Hb level is associated with a greater need for urgent status for heart transplantation.²⁷

Acute Myocardial Infarction
Many treatment advances have improved outcome in acute myocardial infarction (AMI), but this disease continues to have a high mortality risk in the elderly. The potential for anemia to worsen AMI outcome is clear, but the frequency and impact of reduced Hct in this condition had not been well investigated until the recent work of Wu and colleagues.²⁸ These investigators noted a strong adverse association between 30- day mortality and admission Hct in a retrospective study of 78,984 Medicare beneficiaries =65 years. Both adjusted and unadjusted analysis suggested that patients with admission Hct values of 39.1% to 48% had a substantially lower 30-day mortality rate than did patients with lower admission Hct values. For example, the 30-day survival rate was 82.8% in patients with the highest admission Hct values, 70% for patients with admission Hct values of 30.1% to 33.0%, and 64.1% for patients with admission Hct values of 27.1% to 30%. In addition, anemia sufficient to affect prognosis was found to be much more common than previously reported. By the criteria of Hct <39%, 43.4% were anemic, and 4.2% had Hct <30%. These findings suggest that anemia may be an important and underrecognized risk factor in patients with AMI.²⁹

Cancer
Symptomatic cardiovascular disease is not uncommon in patients with cancer. Signs and symptoms of cardiac disease in patients with cancer include exertional dyspnea, tachycardia, palpitations, and increased pulse pressure.³⁰ Structural changes, namely cardiac enlargement and eccentric hypertrophy, have also been reported. Anemia is common in patients with cancer and appears to play a major role in the development of cardiac symptoms in patients with malignancy. The severity of these symptoms is dependent not only on the degree of anemia but also on other patient characteristics, such as age, type of malignancy, and underlying pulmonary and cardiac function.³⁰

Beneficial Effects of Anemia Management

CKD
A number of favorable cardiovascular effects have been observed in patients with CKD whose anemia has been treated. A recent report by London and colleagues demonstrated that treatment directed toward lowering blood pressure and reversing anemia was associated with a reduction in left ventricular mass and favorable outcomes during long-term follow-up in a cohort of 153 patients receiving dialysis.³¹ Augmentation of Hct to within the normal range, target 40%, was associated with significant reductions in left ventricular mass index (LVMI), a measure of LVH, that were superior to those observed with partial anemia correction, target 30% (P <0.01).³² The relationship between anemia treatment and improvements in LVMI was also observed in several small studies that used Hb as a measure of anemia.^33-36

Treatment of anemia in ESRD patients undergoing dialysis has also been associated with improvements in myocardial ischemia. Results of a small study conducted by Wizemann and colleagues showed that correction of Hct from 25% to 35% led to an 81% reduction in ST-segment depression during stress testing, as well as to significant increases in exercise duration (mean 362 s to 489 s, P <0.01) and maximum workload achieved (mean 79 W to 104 W, P <0.01).³⁷

CHF
Preliminary studies show that correction of mild anemia in patients with severe CHF has beneficial effects. In an uncontrolled study, Silverberg and colleagues used a combination of subcutaneous epoetin (mean dose 5,227 IU/week) and intravenous iron (mean dose 185.1 mg/week) to correct anemia in 26 patients with persistent, severe heart failure (all NYHA class III or IV).³⁸ Treatment resulted in improvements in mean Hct (from 30.1% to 35.9%, P <0.001) and mean Hb (from 10.2 g/dL to 12.1 g/dL, P <0.001). Serum iron and iron saturation levels improved as well. Twenty-four of the 26 patients experienced functional improvement, with the mean NYHA functional class decreasing from 3.7 prior to treatment to 2.7 at the end of the study. Patients also showed improved renal function and decreased use of oral and intravenous furosemide. Furthermore, patients required fewer hospitalizations, with an overall decline in hospitalizations of 91% when compared to a similar time period prior to study treatment.

In a second controlled but unblinded study by these investigators, correction of anemia with epoetin and intravenous iron was compared to no anemia correction in 32 patients with moderate to severe heart failure. In this study, correction of anemia to a Hb level of =12.5 mg/dL improved NYHA functional classification (mean increase of 42%), reduced the need for oral and intravenous diuretics (91% and 51%, respectively), and reduced the number of hospitalization days by 79%. In contrast, patients with untreated anemia showed a decline in NYHA functional class (mean decrease of 11%), increased need for oral and intravenous diuretics (mean increases of 29% and 28%, respectively), and a 58% increase in hospitalizations.²⁰

Preliminary data in a pilot study of patients with severe heart failure by Mancini and colleagues demonstrated that correction of anemia with epoetin improved exercise capacity.³⁹ This controlled study involved 22 anemic patients (mean baseline Hb of 10.9 g/dL) with severe left ventricular dysfunction (LVEF22 ± 4%) who were randomized in a 2:1 fashion to either no treatment or 5,000 to 10,000 units of epoetin given subcutaneously per week for 3 months. From baseline to the end of study, these investigators demonstrated a significant improvement (P <0.05) in maximal oxygen consumption during exercise treadmill testing in the 14 patients who received erythropoietin therapy. In contrast, no change was found in maximal oxygen consumption during a similar period of follow-up of eight control patients. Favorable trends were also noted in the treated group on 6-minute-walk testing and assessment of quality of life by the Minnesota Living with Heart Failure questionnaire. The augmentation of exercise performance in the patients treated with erythropoietin was associated with a change in Hb from 10.9 g/dL at baseline to 14.3 g/dL after 3 months of therapy. In contrast, Hb concentration was stable in the control group.

AMI
The data of Wu and colleagues suggest that transfusion, presumably by improving anemia, may be beneficial in elderly patients hospitalized for AMI.²⁸ Although the study was retrospective and the results must be interpreted with caution, the findings of benefit from transfusion were striking.

Transfusion was associated with a reduced mortality rate in patients with Hct <30% and may be effective even in patients with Hct as high as 33%. Additional studies are needed, but these findings provide evidence that treatment of anemia may be an important component of therapy for AMI in certain patients.

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