Evaluation of Patients Suspected of Having Heart Failure

Symptoms. Thorough detection and evaluation of symptoms is critical in the assessment of patients suspected of having HF. The most common symptoms are dyspnea and fatigue from fluid retention, the inability to adequately augment cardiac output and oxygen delivery during exertion, or peripheral factors such as abnormal respiratory and skeletal muscle structure and function. These often manifest as exercise intolerance or a reduction in the intensity of usual activities. Signs of HF relate to manifestations of fluid retention. Dyspnea is typically noted during activity but may be severe enough to be present at rest. Dyspnea may be intermittent even when present at rest or manifest as periodic breathing (e.g., Cheynes-Stokes respiration).26 Patients whose cardiac dysfunction evolves chronically may reduce their activity to minimize symptoms.27 Comparing current activity level with exercise tolerance in the past may be helpful in detecting a decline in functional capacity. A patient's functional capacity should be judged with allowance for age and level of conditioning. Congestion may take many forms. Orthopnea and paroxysmal nocturnal dyspnea are symptoms of elevated left heart filling pressures that are more specific to underlying central congestion. These patients may or may not have visible edema. Peripheral edema occurs in the presence of elevated right-sided filling pressures, together with impaired renal handling of sodium and water. Significant volume overload typically is associated with substantial functional incapacity, yet patients may present with fatigue or exercise intolerance and manifest no signs of fluid retention. Symptoms may occur in isolation or not be classically related to physical signs. Nocturnal symptoms may predominate, whereas daytime symptoms, such as dyspnea on exertion, may be absent.

Less Common Presenting Symptoms. Patients may report nocturnal wheezing or cough, which can reflect fluid overload. In patients receiving angiotensin-converting enzyme (ACE) inhibitors, worsening cough should not be assumed to be drug-related, because it may be a manifestation of increasing left heart filling pressures (Section 7). Patients with severely decompensated cardiac failure may present with gastrointestinal symptoms representative of hepatic congestion or visceral edema, including early satiety, nausea, vomiting, and right upper quadrant pain.

Elevation of the jugular venous pressure, hepatic enlargement or tenderness or pulsatility, and lower extremity edema are manifestations of elevated right heart filling pressures, associated with impaired renal sodium and water clearance.28-31 They also can be due to hepatic or renal dysfunction, various hypo-oncotic states, as well as venous thromboembolism. If due to cardiac disorders, these findings may be accompanied by a loud pulmonic closure sound, RV heave, and a RV S3 (lower left sternal border) consistent with pulmonary hypertension. A prominent laterally displaced apical impulse is indicative of LV enlargement. Increased left heart filling pressure is suggested by rales, diminished breath sounds, wheezing, and an apical S3 gallop.29

Two forms of natriuretic peptide, BNP and NT-proBNP, have been studied extensively as aids to establish the diagnosis, estimate prognosis, and monitor the response to therapy of patients with acute HF.23,24,32,33

Measurement of these peptides has been proposed in cases of acute dyspnea where the diagnosis of HF is uncertain, as evident from large, multicenter investigations.23,24,33 The diagnostic accuracy of BNP, using a cutoff value of 100 pg/mL, was 83% relative to the assessment made by the independent cardiologists, whereas the negative predictive value of BNP for HF when levels were <50 pg/mL was 96%. As expected, measurement of BNP/NT-proBNP appeared to be most useful in patients with an intermediate probability of HF. Plasma NT-Pro BNP cut points of >450 pg/mL for patients younger than 50 years of age, >900 pg/mL for patients age 50-74 years of age, and >1800 pg/mL for patients 75 years or older were equally sensitive and specific for diagnosing HF; with <300 pg/mL providing 98% negative predictive value for ruling out HF.23,33

BNP was found to be predictive of HF when LV function was depressed or preserved, but cannot reliably distinguish between the two.34 In patients with HF associated with preserved LVEF, the BNP cutoff value of 100 pg/mL still had a sensitivity of 86% and a negative predictive value of 96%.

BNP and NT-proBNP levels increase with age, more so in older women or in those with underlying renal insufficiency, in which case the same cutoff ranges may not provide the same degree of specificity for the diagnosis of HF, especially in elderly women with dyspnea.35 However, BNP and NT-proBNP levels should be interpreted with some caution in patients with morbid obesity as they may have lower than expected plasma BNP/NT-proBNP levels.36-38

A number of signs and symptoms of HF are nonspecific, particularly shortness of breath, which may reflect underlying pulmonary disease or physical deconditioning.26 Recognizing this lack of specificity is particularly important in a general practice setting where patients often present with noncardiac causes of shortness of breath or edema. In patients with dyspnea who do not present with clear signs of HF, the possibility of a pulmonary pathology, including pulmonary embolism, should be considered and evaluated. Spirometry, chest computed tomography, ventilation-perfusion lung scan, or pulmonary angiography should be performed as clinically indicated. It is important to recognize that sleep apnea and HF frequently coexist.39-42 In patients with fatigue who are without clear signs of HF, physical deconditioning, sleep apnea, hypothyroidism, and depression should be considered as potential causes. Edema may be due to calcium channel blockers, other drugs (e.g. thiazolidinediones, non steroidal anti-inflammatory drugs [NSAIDs], pregabalin), hypoalbuminemia, or venous stasis.

Characteristic Symptoms. The presence or absence and severity of characteristic symptoms of HF, including those related to exercise tolerance and fluid overload, should be documented in all patients undergoing initial evaluation.

Comorbidities. Symptoms of comorbidities commonly associated with HF should be sought. These include angina,43 symptoms of sleep-disordered breathing, presyncope, or syncope.

Physical Examination. The physical examination should focus on the detection and etiology of structural heart disease, current volume status, and the severity of HF, as a guide to initiating therapy and a baseline to gauge the effect of that therapy. Height and weight should be recorded. Supine and upright vital signs should be taken to assess for orthostasis. Presence of an S3 gallop and elevation of jugular venous pressure are invaluable specific markers of elevated cardiac filling pressures. A positive Kussmaul can be a flag for restrictive disease or significant HF.

Murmurs such as those of aortic stenosis or mitral regurgitation may provide clues to the etiology of LV dysfunction. Murmurs of tricuspid regurgitation and mitral regurgitation vary depending on the degree of pulmonary or systemic pressure, respectively, volume overload, ventricular dilatation, and failure of leaflet coaptation or elevated pulmonary pressures.

The physical examination has limitations. Pulmonary rales are an insensitive indicator of elevation in pulmonary venous pressure, unless they occur abruptly.27 Overt pulmonary edema rarely occurs where left heart filling pressure is chronically elevated, as the pulmonary vasculature adapts with increased lymphatic drainage. Ascites is common in patients with advanced HF (with contributing right HF), but it may be difficult to appreciate on physical examination. Although abdominal complaints can be misleading, history often is a better indicator of excess abdominal fluid than physical examination. Hepatojugular reflux is a sensitive indicator of volume expansion and may be demonstrated in states of RV dysfunction.31

Functional Assessment. Determination of baseline exercise and functional limitation is important during the initial evaluation of patients with established HF. Decisions regarding hospitalization and response to medications and other interventions are aided by estimation of the degree of limitation present at the first evaluation.

A number of strategies can be employed to assist in these estimates, including 6-minute walk test distance.44 One common, time-tested, and simple metric is the NYHA functional classification, which is shown in Table 4.7. 45 Although NYHA class is subjective, numerous longitudinal studies have shown the prognostic power of this determination, and serial evaluation is helpful to gauge response to therapy. Therapeutic recommendations often are directed toward patients within particular NYHA classes, based on use of this indicator as an entry criterion for clinical trials. Success of therapy may be indicated by improvement of at least 1 functional class.46-49

Background: Initial Diagnostic Testing

Electrocardiogram and Chest X-Ray. The electrocardiogram (ECG) provides important information on acute ischemia, prior MI, conduction abnormalities, arrhythmias, and ventricular hypertrophy.50 A chest radiograph may show evidence for cardiac chamber enlargement, increased pulmonary venous pressure, interstitial or alveolar edema, pleural effusions, valvular or pericardial calcification, or coexisting lung disease.

Laboratory Evaluation. The complete blood count may show anemia.51,52 Hyponatremia, from free water retention, may reflect elevated serum vasopressin levels and activation of the renin-angiotensin system.53,54 Hyponatremia, which has been associated with poor prognosis,55,56 may also result from excessive diuresis, but more often indicates severe HF with excess total body salt and water. Elevated serum creatinine may not only reflect important underlying renal impairment but may also represent a prerenal state from reduced cardiac output, venous congestion, intraabdominal hypertension or excessive diuresis.57-59 Renal dysfunction is associated with a worse prognosis.60-63 Prerenal azotemia is usually associated with a disproportionate increase in blood urea nitrogen. If creatinine is disproportionately elevated, it generally indicates intrinsic renal disease. Hypoalbuminemia contributes to low plasma oncotic pressure and edema formation. An abnormal urinary sediment may suggest glomerular disease or infection, and proteinuria may play a role in low oncotic pressure and edema formation. Hyper- or hypothyroidism can precipitate or aggravate ventricular dysfunction and clinical HF and may be clinically occult in the elderly. A lipid profile is valuable in patients with significant risk factors for or a documented history of coronary artery disease.

Determination of Etiology. Initial assignment of HF etiology should be as specific as possible. Significant differences in prognosis are commonly noted among the various etiologies of HF, and identification of specific etiologies, such as ischemic heart disease, may trigger specific directions for evaluation and treatment (Section 13). A number of common etiologies dominate the causes of HF in most practice settings. Ischemic heart disease remains a common cause, especially among patients with reduced LVEF.43

Background: Common Etiologic Factors

Coronary Artery Disease. Patients with evidence of a MI, coronary artery bypass graft surgery, or percutaneous angioplasty or patients who have coronary artery narrowing of greater than 70% in at least 1 artery are most likely to have an ischemic cardiomyopathy.64 On the other hand, the mere presence of atherosclerotic coronary artery disease may not necessarily explain the underlying etiology if cardiac dysfunction is out of proportion to the degree of coronary artery disease. Patients with initially established non-ischemic cardiomyopathy can also develop progressive coronary artery disease, leading to adverse clinical outcomes, such as sudden cardiac death.

Hypertension. Population-based analyses have shown hypertension to be the most important population-attributable risk for HF.5,65 Hypertensive or previously hypertensive patients with a non-dilated left ventricle, preserved LVEF, left atrial enlargement, and concentric LV hypertrophy are most likely to have hypertension as the principal etiology for HF. Among all hypertensive patients with HF, elevated blood pressure should be presumed to contribute to both the cardiovascular pathology and ongoing clinical manifestations of the disease.

The assignment of hypertension as an etiology, particularly of LV systolic dysfunction, has been challenged of late. Clearly, hypertension often is associated with ischemic heart disease and typically is not considered primary in these cases. Documentation of the presence of hypertension may be difficult in many cases of apparently idiopathic cardiomyopathy unless the medical history is carefully reviewed. Many patients with a history of hypertension will not be hypertensive when presenting with systolic dysfunction. Likewise, hypertension may emerge as ventricular function improves with institution of proper medical therapy. In any event, close observation for the development of hypertension is warranted during follow-up.

Alcoholic Cardiomyopathy. Careful history should be directed to determining the quantity of alcohol consumption. In the absence of a clear alternative, an alcoholic etiology is likely among patients with a dilated left ventricle and history of consuming excessive amounts of alcohol.

Valvular Disease. In patients with chronic valvular disease, physical findings may not be characteristic because of low cardiac output. This is especially true of patients with "low gradient aortic stenosis." A history of known valvular or rheumatic heart disease should be sought. Detection of occult valvular disease is one reason for the importance of routine echocardiography as part of the evaluation process.

Idiopathic and Familial Dilated Cardiomyopathy. A number of patients have no apparent cause for their HF despite careful clinical evaluation. The label idiopathic cardiomyopathy represents a diagnosis of exclusion, and less common causes should be sought as indicated below. A family history of cardiomyopathy should be solicited, especially if non-ischemic cardiomyopathy is associated with conduction system disease and arrhythmias. A finding of idiopathic cardiomyopathy might warrant cardiovascular testing in first- and second-degree relatives.66-68 Apical ballooning ("tako-tsubo") cardiomyopathy is a transient syndrome with profound anteroapical dysfunction of unclear etiology and associated with emotional stress or high catecholamines surge. Table 4.8 lists physical and laboratory findings that can point to less common etiologies.

Familial Hypertrophic Cardiomyopathy. Hypertrophic cardiomyopathy is an autosomal dominant condition with both genotypic and phenotypic variability, and patients with this condition may present with dyspnea or syncope. Echocardiography is an effective diagnostic approach. Genetic testing is often indicated.68

Peripartum Cardiomyopathy. HF occurring 1 month before or within 5 months of delivery, with no prior patient history of heart disease or other etiology of cardiomyopathy, is generally labeled peripartum cardiomyopathy.

Chagas Cardiomyopathy. In patients from Latin America presenting with electrocardiographic and echocardiographic manifestations of "ischemic" cardiomyopathy, but who are found to have no significant coronary artery disease on angiography, the diagnosis of Chagas cardiomyopathy should be considered, and Trypanosoma Cruzi titers checked, if they come from an endemic region (e.g., Central or South America).

Endocrine Abnormalities. Pheochromocytoma should be considered in patients with hypertension that is particularly difficult to manage or is characterized by severe fluctuations in blood pressure. Because hypo- or hyperthyroidism can exacerbate HF and, on rare occasion, can represent the principal cause of HF, thyroid-stimulating hormone should be measured. Acromegaly is a rare, but well-recognized, finding in cardiomyopathy and may be uncovered by obtaining a history of increase in jaw, hand, or foot size, or by comparison of the patient's current features with dated photographs. Diabetes mellitus is commonly associated with the development of HF, especially in those with microvascular diseases such as retinopathy or microalbuminuria.69 Diabetes mellitus can contribute directly to the development of HF, via its role as a risk factor for coronary artery disease, or secondary to diabetic agents such as thiazolidinediones that cause fluid retention (see Section 3 for a full discussion of the contribution of diabetes to the development of HF).

Cardiotoxin Exposure. Anthracyclines and occasionally other anti-cancer agents may result in cardiomyopathy, depending on the dose received.70,71 In rare cases, sulphur containing drugs and a number of other agents, including some antibiotics, may initiate an allergic inflammatory reaction leading to eosinophilic myocarditis and decline in heart function.72 Dating the onset of HF to the initiation of these agents will be helpful.

Radiation Therapy. Chest radiation can affect all cardiac structures, including the pericardium, myocardium, coronary arteries and heart valves, and result in a constrictive/restrictive cardiomyopathy, valvular heart disease and/or ischemic heart disease. Ideally, evaluation and management of radiation-induced heart disease should involve a HF specialist and/or cardiac surgeon with expertise in cardio-oncology.73

Exposure to Illicit Drugs. The use of stimulant drugs such as cocaine and methamphetamine may lead to the development of HF.74-77 Patients should be educated on the cardiovascular risks of using these agents.

Drugs Associated With HF Exacerbation. Some pharmacologic agents, including selected calcium channel blockers and antiarrhythmics, may depress cardiac function and increase the likelihood of HF or exacerbation of preexistent or subclinical heart dysfunction.78,79 NSAIDs have been associated with an increased risk of HF hospitalization, and they should be recognized as a causative factor for HF exacerbation and avoided in these patients.80 Thiazelinediones and pregabalin are also associated with fluid retention in patients with HF, and they are not recommended in patients with symptomatic HF.81,82 Tumor necrosis factor antagonists have also been associated with new onset and/or exacerbation of existing HF.83

Connective Tissue Disorders. Systemic lupus erythematosus, scleroderma, and other connective tissue disorders may represent a cause of HF. Vasculitis, hypertension, systemic lupus erythematosus, pericardial involvement, and renal impairment all may contribute to the syndrome of HF. Scleroderma may be associated with myocardial fibrosis with restrictive physiology. In the presence of characteristic skin changes, arthritis, or other organ system involvement, serum antinuclear antibody and rheumatoid factor should be measured.

Toxin Exposure. Lead, arsenic, and cobalt are three toxins that may cause progressive myocardial dysfunction. A history of consumption of lead paint or drinking of well water may provide clues to this unusual cause.

Myocarditis (see also section 16). Rapidly progressive cardiomyopathy, including a rapidly deteriorating clinical condition, should raise suspicion of active myocarditis, including giant cell myocarditis, and represents an indication for consideration of endomyocardial biopsy.84 Myocarditis may be characterized with a subclinical onset or gradual deterioration. Hepatitis C or HIV infection may be a cause of myocarditis, and there should be a low threshold for measurement of viral serology.85-88

Nutritional Deficiencies. Beriberi (thiamine deficiency) may appear in individuals on fad diets or those hospitalized in intensive care units receiving inadequate nutrition. Patients with protein-losing enteropathy due to right HF may develop thiamine deficiency. Selenium deficiency has been recognized as a potential etiology.

Amyloidosis. HF with preserved LVEF and minimal or no LV dilatation, coupled with increased LV and RV wall thickness by echocardiogram, despite normal or diminished QRS voltage on ECG, should raise suspicion of amyloidosis.89 Serum and urine immunoelectrophoresis should be performed, along with measurement of serum free light chains, and confirmation with endomyocardial biopsy (and in some cases genotyping) may be warranted to determine the presence and subtype of amyloidosis involved as they may have different prognosis and management strategies. In particular, specific testing for the presence of transthyretin deposition (familial or wild-type) may identify subtypes that are amenable to transplantation considerations. Cardiac magnetic resonance imaging (MRI) can also aid with the diagnosis and prognosis of cardiac amyloidosis.

Hemoglobinopathies. Repeated transfusions from chronic hemolytic anemia may result in iatrogenic iron overload.

High Output States. Hyperthyroidism, arteriovenous (AV) malformations (rarely), large AV fistulas used for dialysis, or sepsis may result in severe volume overload and high output failure, characterized by preserved LVEF with increased ventricular volumes. HF related to sepsis and other critical acute illnesses is usually a result of transient LV dysfunction that is often self-resolving.

Tachycardia Mediated Cardiomyopathy. Several types of tachycardias including ectopic atrial tachycardia, permanent junctional reciprocating tachycardia (PJRT) using an accessory pathway, atrial fibrillation with a rapid ventricular response, incessant idiopathic ventricular tachycardias, and frequent premature ventricular beats have been associated with the development of a reversible dilated cardiomyopathy. Although conclusive studies are lacking to determine the upper limit of heart rate that may be associated with the development of a cardiomyopathy, a general consensus is that persistent tachycardia >110 beats per minute is required to induced cardiomyopathy. In addition, frequent premature ventricular contractions (PVCs) (20-30% of all beats or >10,000 per 24 hour)90,91 may also be associated with the development of cardiomyopathy.92,93 The optimal level of rate control to prevent the development of cardiomyopathy in patients with atrial fibrillation is not known. In general, a resting ventricular response of 60 to 80 beats per minute and a ventricular response between 90-115 beats per minute during moderate exercise have been suggested.94 The AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) trial targeted heart rates of <=80 bpm at rest, <=110 bpm during a 6 minute walk test, or an average heart rate of 100 beats per minute over at least 18 hours of continuous ambulatory monitoring.95

Sarcoidosis. Sarcoid can mimic many things; it commonly is associated with conduction abnormalities and ventricular tachyarrhythmias. Hilar lymphadenopathy may be a clue to the diagnosis of sarcoidosis. It can be confirmed by endomyocardial biopsy, although false negatives are frequent and a negative biopsy does not exclude a diagnosis of sarcoidosis. Cardiac MRI or specialized positron emission tomography - computed tomography (PET-CT) protocols may help to determine the presence of inflammation.

Hemochromatosis. In the setting of dilated cardiomyopathy, darkened skin, and diabetes, hemochromatosis should be excluded using ferritin. In acute inflammatory states, when ferritin is elevated, other tests, such as iron, iron saturation, and total iron-binding capacity, may be considered. Cardiac MRI may provide reliable accuracy in determining cardiac involvement of iron deposition.

Treadmill exercise testing, with or without measurement of oxygen uptake, to assess functional capacity is not routinely required in the evaluation of patients with a known diagnosis of HF. Nevertheless, there are a number of clinical circumstances in which such testing is beneficial.96 Exertional dyspnea and exercise intolerance may be due to noncardiac causes, especially pulmonary. When there is a disparity between symptoms and objective findings of HF, exercise testing with measurement of expired gases to determine peak oxygen consumption may be useful.

Measurement of peak oxygen uptake may be of assistance in determining candidacy for cardiac transplantation by quantifying functional limitation and adding prognostic information.97 There is no uniform agreement on a cutoff in peak oxygen uptake that constitutes an absolute criterion for candidacy for transplantation. A value of <10 mL O2 kg/min denotes severe functional incapacity and poor prognosis, whereas a value of <14 mL O2 kg/min indicates a patient with underlying advanced HF in whom advanced therapeutic options such as transplantation or ventricular assist devices may be considered.98 The test should be performed after optimizing medical therapy. Several studies suggest that measuring peak oxygen uptake may be less useful in predicting prognosis in patients on beta blockers.99,100 It is commonly recognized that women have lower peak oxygen uptake than men. In younger individuals (<50 years of age) and women, percent of predicted peak VO2 <=50%, or a minute ventilation equivalent of carbon dioxide production slope (VE/VCO2) of >35 are also indicators of poor prognosis and can be considerations for transplant candidacy.98 In obese subjects a calculation of VO2 by lean body mass may also be helpful.98