Many patients with chronic heart failure also HYPERTENSION have a range of comorbid conditions that both contribute to the etiology of the disease and may Hypertension contributes pathogenetically to have a key role in its progression and response the development of systolic and diastolic heart to therapy. This undoubtedly relates to heart fail-failure. As well as being a major risk factor for ure being predominantly a disease of the elderly ischemic heart disease, hypertension can also and driven by risk factors, which are important lead directly to the development of chronic comorbid conditions in and of themselves. heart failure by afterload-induced cardiac hypertrophy and impairment of diastolic function.1,2 Early investigations of the characteristics of patients with chronic heart failure, such as the Framingham study, cited hypertension as the most frequent comorbidity.3 However, in recent intervention trials, hypertension is cited less frequently as a comorbidity and the underlying etiology of chronic heart failure. About 15% of participants in Studies Of Left Ventricular Dysfunction trial (SOLVD) had diastolic blood pressure above 90 mm Hg on entry, but other studies have not reported on this issue.4 It is likely that recent trials have underestimated the contribution of hypertension to the development and progression of chronic heart failure. Blood pressure falls as systolic chronic heart failure develops such that the contribution of hypertension to the failure syndrome may be underappreciated. Hypertension is also a major risk factor for ischemic heart disease, but with the ischemic contribution to heart failure listed as the primary cause, the underlying hypertension may be relegated to a secondary role and not acknowledged as a comorbidity. The effect of antihypertensive therapies in limiting the development of chronic heart failure in patients with essential hypertension supports a major contribution of this comorbidity to onset and progression of chronic heart failure.5–8

Intervention Studies

Placebo-controlled studies have examined the impact of antihypertensive therapy in the prevention of chronic heart failure amongst patients with elevated diastolic blood pressure and those with isolated systolic hypertension.5–8 These studies have consistently demonstrated impressive reductions in the subsequent development of chronic heart failure amongst such patients.

Although the etiology of diastolic heart failure is incompletely understood, it is likely that hypertension is a major contributor. Therefore, a major goal of therapy in the hypertensive patient with diastolic heart failure should be the reduction of elevated blood pressure to target levels. Other key goals of therapy in this setting include avoidance of fluid overload (whilst being vigilant for iatrogenic underperfusion), recognizing and treating ischemia and arrhythmia, and correcting underlying contributory valvular disease. A number of studies conducted primarily in patients with chronic heart failure and diastolic dysfunction are currently in progress or have recently reported their findings. These include the Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) study with irbesartan, the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity-Preserved (CHARM-Preserved) study with candesartan cilexetil, Study of the Effects of Nebivolol Intervention on Outcomes and Hospitalization in Seniors with Heart Failure (SENIORS) with nebivolol, and the Perindopril for Elderly People with Chronic Heart Failure (PEP-CHF) study with perindopril.9–11 These studies enrolled patients with hypertension as a major comorbid factor, such as in the CHARM-Preserved study where 64% of the study population had preexisting or concomitant hypertension at baseline.

ISCHEMIC HEART DISEASE

Coronary artery disease features prominently as an etiological factor in chronic heart failure patients.12 As with hypertension, it is also likely that the contribution of ischemia to chronic heart failure is underreported.13 Many patients enrolled in chronic heart failure trials may have ischemia but do not have a high level of documentation of this comorbidity. Furthermore, patients with active ischemia are often excluded from entry into these trials.

Coronary artery disease may lead to heart failure through a variety of mechanisms. Most dramatically, extensive myocardial necrosis will result in pump failure. Infarction of smaller areas may lead to regional contractile dysfunction and adverse remodeling with myocyte hypertrophy, apoptosis, and extracellular matrix deposition. In addition, transient reversible ischemia may occur with episodic dysfunction even in the presence of “normal” resting ventricular function.14

Thus, patients with myocardial ischemia may have hibernating (but potentially viable) myocardium.15,16 Ventricular function may therefore be improved by myocardial revascularization in this setting.17,18 In the CHRISTMAS study, over 50% of ischemic chronic heart failure patients had evidence of hibernation affecting two or more segments on echocardiography.19

However, this has not as yet been tested in a rigorous manner. Revascularization in such patients may result not only in improved ventricular function but also in long-term symptomatic and prognostic benefits.20,21

Many of the pathogenetic factors that contribute to endothelial dysfunction and atherosclerosis (and thus ischemia) are also involved in the ongoing progression of chronic heart failure.22 These factors include activation of the renin-angiotensin-aldosterone, sympathetic, and endothelin systems.23 Therefore, a component of the beneficial effects of neurohormonal antagonists in the management of chronic heart failure may occur on the basis of improvements in underlying ischemia. For example, angiotensinconverting enzyme (ACE) inhibitors improve coronary endothelial function (Trial on Reversing Endothelial Function [TREND]) and reduce development of chronic heart failure in patients at high risk of cardiovascular disease (Heart Outcomes Prevention Evaluation [HOPE]).24,25 Similarly, the SOLVD and Survival and Ventricular Enlargement (SAVE) studies (in patients with systolic ventricular dysfunction) demonstrated both reductions in ischemic events and heart failure hospitalizations.26,27 In the Carvedilol Postinfarction Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial, patients with postmyocardial infarction (MI) ventricular systolic dysfunction derived benefit from the b-blocker carvedilol, both in terms of subsequent ischemic endpoints and chronic heart failure-related events.28

Several analyses have examined differences in responses to pharmacological therapies between ischemic and nonischemic etiologies of heart failure. In some studies, such as the Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy (CHF-STAT) (amiodarone), the Prospective Randomized Amlodipine Survival Evaluation (PRAISE I) (amlodipine), and an early b-blocker study, the magnitude of the benefit appeared to be greater amongst patients with a nonischemic etiology.29–31 In contrast, however, other trials have not reported substantial differences in clinical response between these etiologies (Cardiac Insufficiency Bisoprolol Study II [CIBIS-II], Carvedilol Prospective Randomized Cumulative Survival trial [COPERNICUS], Randomized Aldactone Evaluation Study trial [RALES], Evaluation of Losartan in the Elderly [ELITE II], and Valsartan Heart Failure Trial [Val-HeFT]).32–36

DIABETES MELLITUS

Diabetes is a frequent and important, but commonly overlooked, comorbidity in patients with chronic heart failure. Subjects with diabetes are not only at higher risk of developing chronic heart failure but also have worse symptoms for their level of systolic function and a higher mortality compared with their nondiabetic counterparts.37–39

The Framingham study first reported an overrepresentation of diabetic patients amongst chronic heart failure patients, such that 14% of men and 26% of women with chronic heart failure were noted to have concomitant diabetes.40 In a further report from Framingham, in which 5209 middle-aged community dwellers were followed prospectively for 10 years, diabetes was associated with a twofold increase in chronic heart failure in men and a fivefold increase in chronic heart failure in women.41 Moreover, this increased risk of chronic heart failure persisted after adjustment for other potential confounders such as known coronary artery disease, age, blood pressure, and cholesterol.

Community-based studies in the elderly have also reported that diabetes was an independent risk factor for the development of chronic heart failure with relative risks of 1.7–2.9.42–44 In the U.K. Prospective Diabetes Study (UKPDS), the development of chronic heart failure was examined over a 10-year period in almost 4000 community-based, middle-aged type 2 diabetic patients.45,46 In these subjects, the absolute risk of hospitalization for chronic heart failure was 3–8.1 per 1000 patient years, depending on the assigned treatment group. This risk can be compared with those of nonfatal MI, nonfatal stroke, and renal failure at 7.5–9.5, 4–8.9, and 0.6–2.3 per 1000 patient years, respectively, in the same study.

Three major factors contribute to the high prevalence of chronic heart failure in diabetes: hypertension, coronary artery disease, and diabetic cardiomyopathy. Patients with diabetes characteristically develop premature atherosclerotic coronary artery disease, which is often widespread, asymptomatic, and presents late.46 Indeed, patients with diabetes are two to three times more likely to develop chronic heart failure following MI, and diabetic women are at particularly high risk.47 Hypertension, another risk factor for the development of chronic heart failure, is present in 71–93% of patients with type 2 diabetes.48 Both experimental and clinical studies have provided evidence for the existence of a diabetic cardiomyopathy, independent of large vessel disease.39,49,50 The clinical manifestations of this cardiomyopathy are poorly understood, with asymptomatic diastolic dysfunction a common finding on echocardiographic investigation in diabetic patients.49 The role of autonomic dysfunction, endothelial dysfunction and abnormal energy metabolism, and the development of chronic heart failure in the diabetic patient is less well understood.51

The presence of chronic heart failure as a comorbidity should be taken into consideration in the choice of drugs used for the treatment of diabetes. In particular, metformin is contraindicated in the presence of chronic heart failure. Similarly, the thiazolidinediones should be avoided in patients with New York Heart Association (NYHA) III–IV disease and used with caution in patients with less severe chronic heart failure.

Intervention Studies

In the UKPDS, intensive blood glucose control did not significantly reduce the likelihood of macrovascular disease.46 However, this study also examined the risk of complications at different levels of glycemia. In this prospective, observational component of UKPDS, a continuous relationship between glycemic exposure and the development of chronic heart failure was noted with no threshold of risk, such that for each 1% (absolute) reduction in hemoglobin A1c, there was an associated 16% decrease in hospitalization for heart failure.52 Similar findings have also been recently reported in a large cohort study from the United States.53

The UKPDS additionally examined the effect of blood pressure control on the development of chronic heart failure in the diabetic patient. Tight blood pressure control was associated with a 56% reduction in the risk of chronic heart failure.45 As with glycemia, the incidence of chronic heart failure was significantly associated with systolic blood pressure, such that a 10 mm Hg decrease in systolic blood pressure was accompanied by a 12% decrease in chronic heart failure, also with no apparent threshold of risk.54 A number of other intervention trials using angiotensin receptor blockers have also shown a reduction in the development of chronic heart failure in high-risk patients, apparently independent of blood pressure.55 Such studies, which included those in patients with diabetes, hypertension, and left ventricular hypertrophy (Losartan Intervention for Endpoint Reduction [LIFE]) and in patients with diabetic nephropathy (Irbesartan in Diabetic Nephropathy Trial [IDNT] and (Reduction in End Points in Noninsulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan [RENAAL]) highlight the importance of blocking the renin-angiotensin system in the prevention as well as in the treatment of heart failure in diabetes.56–58

Diabetes is a noted comorbidity in between 10% and >30% of participants in clinical trials in chronic heart failure.59 Despite its limitations, analysis of the diabetic subgroup within these trials has provided significant insight into the relationship between chronic heart failure and diabetes and provided information on a range of pharmacological interventions including ACE inhibitors, angiotensin receptor blockers, and b-blockers. For instance, in SOLVD, diabetes was associated with increased mortality, but only in patients with ischemic cardiomyopathy (RR 1.37,

CI: 1.21–1.55, P <0.0001) and not in those with a nonischemic cardiac dysfunction (RR 0.98).60 Fortunately, patients with diabetes and ischemic cardiomyopathy do respond to therapeutic intervention, particularly following acute MI.61

Diabetes, particularly in the presence of chronic heart failure, has traditionally been viewed as a contraindication to the use of b-blocking agents. Nevertheless, b-blockers have been consistently shown to improve prognosis and reduce hospital admissions for systolic chronic heart failure when added to background ACE inhibitor and diuretic therapy. Furthermore, the major chronic heart failure-b-blocker trials have shown similar benefit in the diabetic subgroup such that this class of drug should be strongly considered in treating the diabetic patients with chronic heart failure.62,63

In Val-HeFT, the addition of the angiotensin receptor blocker valsartan, significantly reduced morbidity and mortality in patients with NYHA Class II–IV chronic heart failure, reporting a consistent beneficial effect among predefined subgroups of patients, including those with diabetes.36

Although patients with diabetes were not excluded in RALES, no subgroup analysis is mentioned.34 However, patients with diabetes, in whom hyporeninemic hypoaldosteronism is common, may be at particularly high risk of developing hyperkalemia when an aldosterone antagonist is added to baseline ACE inhibitor therapy and vigilant monitoring of serum potassium is recommended.

CARDIAC ARRHYTHMIAS

Many factors contribute to the frequent development of arrhythmias in chronic heart failure, including ischemia and infarction, electrophysiological abnormalities, myocardial hypertrophy, and the activation of various neurohormonal systems.64 Furthermore, alterations in electrolyte status as well as the proarrhythmic effect of many antiarrhythmic heart failure drug therapies may also contribute.

Ventricular Arrhythmias

Ventricular arrhythmias in patients with chronic heart failure range from benign (asymptomatic premature ventricular contractions [PVC]) to fatal (ventricular fibrillation), with “sudden” death estimated to account for approximately half of all deaths amongst chronic heart failure patients.65 In patients with advanced chronic heart failure, 11% had a prior cardiac arrest plus ventricular tachycardia and an additional 3.4% had a history of ventricular fibrillation.65

The management of ventricular arrhythmias in patients with established chronic heart failure is controversial. While amiodarone is the preferred antiarrhythmic in chronic heart failure patients with severe, symptomatic, and sustained ventricular tachycardia, large-scale trials do not support its prophylactic use in patients with nonsustained asymptomatic arrhythmias.29,64 The antiarrhythmic properties of b-blockers, together with reductions in sudden death with these agents would suggest benefit in reducing lethal arrhythmias.32,33,65

Implantable cardioverter defibrillators (ICDs) have proven beneficial in patients with a high risk of sudden death, for example, those with impaired ventricular function, life-threatening ventricular arrhythmias, or survivors of sudden death.66–68 As some of the studies contributing to the ICD database used electrophysiological entry criteria, for example, the Multicenter Automatic Defibrillator Implantation Trial (MADIT), this approach may also be indicated in selecting chronic heart failure patients for ICD.66 Recently, the MADIT II trial has been terminated because of the benefit of ICDs (compared to standard medical therapy) in patients >1 month post-MI with a left ventricular ejection fraction (LVEF) ≤30% and ≥10 ventricular extrasystoles/hour on Holter monitoring.69 As many ischemic chronic heart failure patients would fit this category, there are major potential cost implications to these observations, despite the relatively small absolute risk reduction observed.

Furthermore, amiodarone has been found to be inferior to ICD in reducing mortality in patients with systolic chronic heart failure of NYHA Class II–III severity.70

Atrial Fibrillation

Atrial fibrillation (AF) is a common concomitant morbidity with chronic heart failure, present in up to a third of all patients enrolled in major intervention trials. While AF is often a consequence of the many etiological factors contributing to chronic heart failure, it may (very rarely) lead to its development, particularly if the ventricular response is not adequately controlled. b-Blockers are frequently used (in conjunction with digoxin) to control ventricular response. Nonetheless, there is some controversy regarding their impact on outcome in patients with AF in the setting of chronic heart failure. In particular, in a subgroup analysis of the CIBIS-II trial of bisoprolol, there was no apparent benefit for active therapy amongst patients with AF, contrasting with the findings for the entire study cohort.71 However, this heterogeneity in response was not observed in other chronic heart failure b-blocker trials such as with carvedilol.72

While there is no evidence that restoring sinus rhythm is superior to controlling the ventricular response in patients with chronic heart failure and AF, both electrical cardioversion and amiodarone, either alone or in combination, are often used.73 The use of other antiarrhythmics is limited by their negative inotropic and proarrhythmic effects, although dofetilide improved AF reversion rates, without increasing mortality, in patients with chronic heart failure.74

Anticoagulation with warfarin should be standard therapy for heart failure patients with concomitant AF, unless contraindicated.63 Far more controversial is the use of thromboprophylaxis in patients with ventricular dysfunction and normal sinus rhythm (see below).

THROMBOEMBOLISM

There is evidence that chronic heart failure is associated with an increased risk of thromboembolism (e.g., because of the frequent presence of thrombi within akinetic segments of failing ventricle and an increased propensity to develop AF). The SOLVD trial clearly demonstrated an increase in the incidence in stroke (mainly thromboembolic) with decreasing ventricular function.75 However, retrospective analyses of studies of antithrombotic therapy in chronic heart failure have yielded conflicting results.

There is an urgent need for prospective studies of anticoagulation in chronic heart failure patients in sinus rhythm, using agents such as warfarin. An early pilot trial, the Warfarin/Aspirin Study in Heart Failure (WASH) study, compared groups taking aspirin, warfarin, and no anticoagulation.76 There was no significant difference between groups within this small study, although there was a tendency towards an increase in hospitalization in the aspirin group. This may be due to adverse interactions between aspirin and ACE inhibitor, offsetting the beneficial effects of the latter.

The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial compared open-label warfarin with blinded antiplatelet therapy (either aspirin or clopidogrel) in patients with NYHA Class II–IV symptoms and an LVEF of <30%.77 The primary endpoint was a composite of all-cause mortality, nonfatal MI, and nonfatal stroke. Unfortunately, the study was truncated before full recruitment had been achieved and, consequently, was underpowered to explore planned primary or secondary endpoints. Nevertheless, hospitalization for heart failure seemed again to be increased in aspirin-treated patients.77

The precise role of inhibitors of adenosine diphosphate (ADP), of activation of platelets (e.g., clopidogrel), and of warfarin in prophylaxis of thromboembolism in chronic heart failure remain uncertain. Similarly, the role of newer agents, such as direct thrombin inhibitors, has not yet been prospectively studied in this condition.

OTHER IMPORTANT COMORBID CONDITIONS

Respiratory Disorders and Sleep Apnea

The interaction between chronic heart failure and concomitant respiratory disease is an important one. Many patients with heart failure are commonly misdiagnosed as having airflow obstruction based on overlapping symptomatology (and vice versa). Careful consideration with regard to the possibility that both cardiac and respiratory disease may coexist is critical to the optimal evaluation and thus management of these patients.

b-Blockers are considered to be contraindicated in the chronic heart failure patient with airflow obstruction. In practice, because of the overwhelming benefits of these agents in systolic heart failure, patients with fixed or limited airway reversibility are often given these agents with surprisingly good tolerability.78 It is not clear whether b-1 selective agents offer advantages in this regard compared to nonselective agents such as carvedilol.79

Sleep apnea may be both a cause and consequence of chronic heart failure. Central sleep apnea with Cheyne-Stokes respirations during sleep affects about 40% of patients with chronic heart failure.80 Obstructive sleep apnea also frequently coexists and may also contribute to disease progression.81 Trials of continuous positive airway pressure (CPAP) in such patients have, in the short term, improved autonomic dysfunction and increased LVEF.82,83

Cognitive Dysfunction and Dementia

There is clear-cut evidence that cognitive dysfunction coexists with heart failure.84,85 Chronic heart failure is associated with low cardiac output, which may further compromise cerebral blood flow in a patient with borderline perfusion of their cerebrum. In addition, chronic heart failure is largely driven by vascular disease (at least in Western societies) and cerebrovascular disease is an important contributor to multi-infarct dementia.

Measures of cognitive function have rarely been studied in heart failure trials, unlike recent hypertension trials such as the Systolic Hypertension in Europe (SYST-EUR) trial and the Study on Cognition and Prognosis in the Elderly (SCOPE).8,86 Given the consistent reporting of impaired cognitive function in cross-sectional studies of patients with heart failure, perhaps this should be considered as an end point for future trials of heart failure pharmacotherapy.

Hyperlipidemia

Despite the classical perception of the chronic heart failure patient as being cachectic with low-plasma cholesterol levels, hyperlipidemia in fact coexists with chronic heart failure in a significant percent of patients. In chronic heart failure intervention trials, up to 26% of patients were classified as being hyperlipidemic on entry.87 Of particular interest is whether HMG-CoA reductase inhibitor (statin) therapy may be beneficial in patients with established chronic heart failure. This has never been formally tested in prospective trials, because trials of lipid-lowering therapy have generally excluded patients with significant left ventricular systolic dysfunction.88–90 Furthermore, there is concern regarding these agents lowering ubiquinone (coenzyme Q10) levels, which may be important in maintenance of myocardial function in chronic heart failure.91,92 In addition, maintenance of circulating lipoproteins may be necessary to lower elevated circulating levels of proinflammatory cytokines, which may adversely impact on disease progression.93–95

Nevertheless, as statins beneficially impact coronary artery disease progression, this may translate into long-term benefits in patients with chronic heart failure of an ischemic etiology. Indeed, post hoc, retrospective analyses of major lipid-lowering trials support statin therapy as being of benefit for chronic heart failure. In the Scandianavian Simvastatin Survival Study (4S) trial, simvastatin decreased the rate of development of chronic heart failure following MI as well as the mortality of patients who developed chronic heart failure during the course of the study.96

The impact of statin therapy in patients with established chronic heart failure has been retrospectively assessed in nonrandomized, subset analyses within major chronic heart failure intervention trials. In the Evaluation of Losartan in the Elderly (ELITE) II study, there was a significantly lower mortality in patients receiving statins (10.6%) compared to those who were not (17.6%).97

In this regard, antiapoptotic, endothelial progenitor cell stimulatory, and vascular endothelial growth factor-stimulatory effects, antagonism of proinflammatory cytokines, and antifibrotic effects of statins may contribute to improvement in myocardial function directly and independent of effects on coronary artery disease.98–102 This hypothesis has been supported by animal studies in which a statin improved parameters of ventricular function and reduced pathological fibrosis in the absence of changes in plasma cholesterol.103 Furthermore, some but not all remodeling studies have suggested improvement in systolic ventricular function with statin therapy.104–107

Chronic Anemia

Anemia is common in chronic heart failure, with a mean hemoglobin of 12 g/dL amongst such patients.108 The likelihood of anemia in patients with chronic heart failure correlates with disease severity.109

Small-scale studies of administration of subcutaneous erythropoietin and intravenous iron to patients with chronic heart failure and mild anemia have been shown to produce improvement in patients’ overall clinical status and ventricular function.109,110 A large-scale study to examine the effect of anemia correction with erythropoietin on clinical outcomes has commenced (Reduction of Events with Darbepoetin alfa in Heart Failure [RED-HF]).

Despite the above considerations, the importance of identifying and correcting mild anemia is generally under-recognized within this patient cohort.

Renal Failure

The close relationship between cardiovascular and renal function in normal physiology is also apparent in the setting of disease, where renal dysfunction may develop secondary to cardiac disease or vice versa. As a consequence of accelerated atherosclerotic coronary artery disease, concomitant hypertension, and fluid retention, patients with primary renal disease are at high risk of developing heart failure.111 Alternatively, patients with heart failure often have evidence of kidney dysfunction in the absence of intrinsic renal disease.112 The observed reduction in glomerular filtration rate in chronic heart failure is a consequence of diminished cardiac output, with decreased renal perfusion and intrarenal vasoconstriction accompanied by sodium and water retention.111 Indeed, given this relationship between renal function and cardiac output, it is perhaps not surprising that renal dysfunction is not only an adverse prognostic marker but is a stronger predictor of poor outcome in heart failure than NYHA functional class.112,113

Blockade of the renin-angiotensin system is a cornerstone of both chronic heart failure therapy and renoprotective treatment in patients with both diabetic and nondiabetic kidney disease.58,114 However, as the renal vasoconstriction that develops in the setting of reduced cardiac output is angiotensin II-dependent, treatment with an ACE inhibitor or angiotensin receptor blocker frequently leads to a (usually clinically unimportant) increase in the serum creatinine.

Arthritis and Gout

Patients with chronic heart failure tend to be elderly, and therefore other noncardiovascular conditions of the elderly will frequently coexist.