Anemia of chronic disease is a form of anemia that occurs during chronic illness in response to inflammatory processes. In patients with HF, the hemoglobin level is inversely related to levels of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and soluble TNF receptor, and other markers of inflammation such as C-reactive protein.

Dysfunction of erythropoietin production. Renal dysfunction leads to a decline in erythropoietin production through the loss of erythropoietin-producing cells in the kidney. However, it is unusual to see significant anemia due to renal failure until the glomerular filtration rate (GFR) drops below 20 mL/minute. Activation of the renin–angiotensin system, and the consequent angiotensin-converting enzyme (ACE) inhibition and angiotensin-receptor blockade, also reduces erythropoietin production and causes a modest reduction in hemoglobin.

Treatment

Iron supplementation and investigation for the underlying cause of the deficiency are indicated when frank iron-deficiency anemia is diagnosed.

However, functional iron deficiency associated with elevated inflammatory markers (i.e. anemia of chronic disease) is characterized by adequate iron stores but reduced availability of tissue iron stores for erythropoiesis. Recently, intravenous iron replacement has been shown to improve symptoms, quality of life and exercise capacity in iron-deficient patients with chronic HF.

Erythropoiesis-stimulating agents (ESAs). Trials of ESAs have shown an increased risk of thrombosis in patients with chronic kidney disease (and increased all-cause mortality in trials of patients with malignancy). Therefore, these agents are not recommended as therapy. The exception is in cases of decreased endogenous erythropoietin production due to chronic renal failure.

Pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a common comorbidity in patients with HF, with a prevalence of 10–46%. Conversely, up to 20% of patients with COPD may have undiagnosed HF and up to 40% may have evidence of some LV systolic dysfunction. Cigarette smoking is strongly associated with COPD and coronary artery disease (CAD). It also increases the risk of developing HF by 50%.

Low-grade systemic inflammation is common in patients with COPD and vascular disease, so their coexistence accelerates atherosclerosis and contributes to the increase in adverse cardiovascular events. Furthermore, a reduction in forced expiratory volume in 1 second (FEV₁) in patients with COPD independently predicts cardiovascular mortality even after adjusting for conventional cardiovascular risk factors such as age, cigarette smoking, hypertension, cholesterol and obesity. In patients with HF, COPD increases non-cardiovascular mortality and the overall hospitalization rate.

Natriuretic peptides (type B natriuretic peptide [BNP] and N-terminal hormone of BNP [NT-proBNP]) are produced in response to intracardiac stretch. In patients with dyspnea, normal serum levels of natriuretic peptides (BNP < 100 pg/mL) have high negative predictive value and help to rule out LV systolic dysfunction as a cause of symptoms. Unfortunately, patients with advanced COPD and cor pulmonale often display mild elevation in natriuretic peptide levels.

Echocardiography may provide limited results in up to 50% of patients in view of technical difficulties (poor acoustic windows and endocardial definitions). However, it still remains the initial diagnostic test.

Lung function testing. Airflow obstruction is common in patients with decompensated HF, sometimes resulting in the misdiagnosis and overestimation of COPD severity. With diuresis, mean FEV₁ improves and may even return to normal. Lung function tests should therefore be performed in clinically stable patients without significant pulmonary congestion. Restrictive ventilatory defects are frequent in patients with compensated HF. They mask hyperinflation and obscure diagnosis of COPD in patients with HF.

Prevention and treatment. Respiratory infections are associated with HF decompensation in 10–16% of admissions. Pneumococcal and influenza A vaccinations of elderly patients with HF reduce the rate of hospitalization and associated costs.

In general, concomitant pulmonary and HF therapy is safe, although short-acting β₂-adrenoreceptor agonists and digoxin have potentially negative effects on cardiac and pulmonary function, respectively. Cardioselective beta-blocking agents should not be withheld from patients with COPD as no relevant long-term effects on pulmonary function have been established.

• physiological

• increased sympathetic drive

• endothelial dysfunction

• inflammatory effects – an increase in NFKB1 transcription

• procoagulant effect.

The physiological effects of an exaggerated, negative intrathoracic pressure include an increase in RV preload and a decrease in LV preload with resulting reduction in LV stroke volume. There is also a concomitant decrease in afterload and LV diastolic relaxation. Intermittent elevation of blood pressure accompanying recurrent episodes of apnea and arousal may lead to the development of arterial hypertension. Hypoxia caused by recurrent apnea increases oxidative stress and contributes to further endothelial dysfunction and inflammation. Episodes of inappropriate sinus tachycardia, and atrial and ventricular arrhythmias are common.

Diagnosis. Patients with HF have fewer symptoms of sleep apnea than matched community controls without a cardiac condition, and the two conditions may produce similar symptoms, sometimes leading to delayed diagnosis and treatment of the apnea. Referral for polysomnography should be triggered by a combination of:

• suspicious symptoms (snoring, apnea, unrefreshing sleep, hypersomnolence)

• high-risk clinical features (male, middle aged or older, obese)

• severe underlying cardiomyopathy (LV ejection fraction [LVEF] < 25%)

• willingness to consider treatment.

Prognosis. Untreated sleep-disordered breathing is associated with higher cardiovascular mortality. Moderate-to-severe OSA (apnea–hypopnea index [AHI] > 15) in patients with ischemic cardiomyopathy has been shown to be independently associated with increased mortality (mainly due to sudden cardiac death). A similar association has not been observed in patients without cardiac ischemia. Higher mortality (median survival reduced by 50%) has also been reported in patients with severe LV dysfunction (LVEF < 40%) and CSA.

• oxygen

• continuous positive airway pressure (CPAP)

• bi-level ventilation

• servo-adaptive ventilation (in patients with predominant CSA).

Treatment with CPAP alleviates episodes of OSA and associated physiological consequences that may lead to a reduction in LV afterload and ongoing oxidative stress. However, up to 30% of patients may not be able to tolerate it. Evidence that CPAP has a positive effect on cardiovascular morbidity and mortality in patients with HF is lacking, despite observational studies reporting a decrease in sympathetic nervous activity, and blood pressure and improvement in cardiac performance (LVEF). Hence, the current indications for CPAP in patients with HF and sleep-disordered breathing are limited to management of diurnal hypersomnolence. Disappointingly, a recent study of CPAP in patients with predominant CSA showed an increase in mortality in the treatment group.

Renal disease

Renal dysfunction is frequently found in patients hospitalized with HF and is strongly associated with increased morbidity and mortality. Up to 50% of ambulatory patients with stable HF have some degree of renal dysfunction. Moderate-to-severe renal dysfunction in patients with HF increases the relative mortality risk by 100% (absolute risk > 50% at 5 years). In patients with baseline estimated GFR < 50 mL/min/m² a further drop of 10 mL/min/m² increases mortality by 7%.

Cardiorenal syndrome. The existence of both HF and renal dysfunction in an individual is called cardiorenal syndrome (CRS), which is divided into five types, according to the presentation (acute versus chronic) and primary cause of the syndrome (cardiac versus renal):

• CRS type 1 (acute) – acute decompensated HF leading to acute kidney injury (AKI)

• CRS type 2 (chronic) – chronic HF leading to chronic kidney disease

• CRS type 3 (acute renocardiac syndrome) – AKI leading to acute cardiac dysfunction (HF, arrhythmia or coronary ischemia)

• CRS type 4 (chronic renocardiac syndrome) – chronic kidney disease contributing to cardiac dysfunction

• CRS type 5 (secondary CRS) – combined heart and kidney dysfunction due to an acute (e.g. sepsis) or chronic (e.g. diabetes mellitus) systemic disorder.

Treatment differs for the types. In general, careful patient selection and monitoring are crucial. ACE inhibitors or angiotensin-receptor blockers (ARBs) are safe to introduce in patients with CRS type 1 provided the initial rises in serum creatinine and potassium are less than 30% and 5.6 mmol/L, respectively. These drugs should not be initiated in patients with CRS type 3 or known bilateral renal artery stenosis. Chronic therapy with ACE inhibitors or ARBs should be continued (in CRS types 1, 2, 3 and 4), but with close monitoring of serum creatinine and potassium levels.

Beta-blockers should not be initiated in CRS type 1 as they may precipitate an acute drop in cardiac output and a worsening of both AKI and HF, but their continuous use in CRS types 2, 3 and 4 should not be interrupted.

In CRS type 5, the source of infection should be treated (antibiotics, surgery) and supportive cardiac therapy given, including judicious use of intravenous fluids, vasopressors and inotropic agents. If required, hemofiltration may be preferable to hemodialysis, as the latter may cause shifts in intravascular volume, hypotension, arrhythmia and worsening cardiac function.

Transient abnormalities in liver function tests are relatively common in patients with chronic congestive HF. Elevations in aspartate transaminase (AST), alanine transaminase (ALT) and lactate dehydrogenase (LDH), and rarely an increase in serum bilirubin level, have been found on testing. Progression to end-stage liver disease is rare.

Congestive hepatopathy or ‘cardiac cirrhosis’ is caused by a long-standing elevation in right atrial pressure, as seen in right-sided HF, constrictive pericarditis, pulmonary hypertension and tricuspid valve disease. The primary mechanism of congestive hepatopathy is persistent venous stasis, which leads to hepatic necrosis and fibrosis.

Patients with congestive hepatopathy may develop right upper quadrant pain, anorexia, nausea or vomiting, but the symptoms and signs of HF dominate the disorder. Ascites is a frequent finding. Splenomegaly, jaundice and progression to encephalopathy are rare. Elevations in AST, ALT and serum bilirubin, and prolonged prothrombin time are frequently found on testing. Protein-losing enteropathy with serum hypoalbuminemia may coexist.

The differential diagnoses include alcoholic liver disease, Budd–Chiari syndrome and hepatic vein thrombosis. The effect of congestive hepatopathy on morbidity and mortality is uncertain.

There is no specific therapy except the treatment of the underlying cardiac condition.

Acute ischemic hepatitis has been reported in patients with acute cardiac dysfunction (either new or decompensated chronic HF). It develops in response to a sudden drop in hepatic perfusion resulting from a combination of poor cardiac output and venous congestion.

The condition is characterized by acute hepatocellular necrosis with an increase in serum AST and ALT levels (frequently in the thousands) with accompanying signs (cold periphery, poor urine output, pulmonary congestion) and symptoms (dyspnea, fatigue, nausea, poor appetite) of a low-output state.

Cirrhotic cardiomyopathy may occur in patients with hepatic cirrhosis; it should be suspected in patients with worsening hemodynamic status. Cardiac involvement is mainly subclinical, long standing and generally well tolerated. The elevated cardiac output often found in patients with cirrhosis is caused by splanchnic arterial vasodilation, which results in vascular redistribution and a decrease in cardiac preload (despite intravascular volume expansion). Vascular remodeling, with increased vascular compliance and autonomic dysfunction, has also been reported.

The molecular abnormalities associated with cirrhosis, and the negative effect of mediators of cirrhosis (carbon monoxide, endogenous cannabinoids, nitric oxide and proapoptotic kinases) impact on cardiac physiology (QT prolongation, electrical and mechanical dyssynchrony, inotropic and chronotropic incompetence) and may result in diastolic and systolic cardiac dysfunction. The decompensation of cirrhotic cardiomyopathy may be triggered by a sudden change in volume status (i.e. an increase in preload) and vascular resistance (during sepsis, paracentesis, porto–systemic shunt or transplantation).

No specific treatment or management strategies exist for patients with cirrhotic cardiomyopathy, but they should be aggressively monitored during procedures likely to cause decompensation.

Depression

The illness is fairly common among patients with HF, with a reported prevalence of 10–25% in outpatients and 35–70% in inpatients. Most patients have mild symptoms, with fewer than 20% experiencing moderate or severe depression. Women are more likely to be affected by depression than men. The prevalence of depression is inversely related to the severity of HF (NYHA class).

Prognosis. Depression is associated with non-adherence to medications, poor health-seeking behavior and low social support. It is therefore not unexpected that depression in patients with HF is independently associated with poor prognosis, increased mortality and readmissions to hospital, and use of more medical resources.

In one study, the presence of depression doubled the risk of death and emergency department presentations and increased the total healthcare costs by 29%.

Mechanisms. There are several proposed mechanisms by which depression leads to clinical deterioration and results in worse outcomes in patients with HF. They include:

• neurohormonal activation

• rhythm disturbances

• inflammation

• hypercoagulability

• poor patient adherence

• low social support.

Diagnosis. Initial screening in patients with HF may include the two questions from the Patient Health Questionnaire (PHQ)-2:

‘Over the past 2 weeks, how often have you been bothered by:

(1) little interest or pleasure in doing things, or

(2) feeling down, depressed or hopeless?’

If the patient answers yes to either part then further assessment with the PHQ-9 is indicated. A score of 10 or more on the questionnaire dictates the need for therapy and specialist assessment (psychologist, psychiatrist).

Treatment. In general, therapeutic intervention in patients with depression and HF includes the combination of an antidepressant (selective serotonin-reuptake inhibitor such as sertraline), social support and psychotherapy.