Teaching Points::::CHF

[Ace844]

Hi All,

I thought that I'd post a little something on CHf here for ya...I hope this helps and that we can continue to discuss CHF, management, etc... here in this thread...I remember awhile back "Ridryder," et.al., did a few of these but most likely got too busy to continue to do so. If you all like the idea of "teaching posts" speak up and let us all know!!!!

( credit goes to New Insights into Decompensated Heart Failure; Emerg Med 37(6)18-25:, 2005)

In the past decade a more refined understanding of the pathogenesis of heart failure has emerged to guide therapy. The authors review the science, point out the clinical pitfalls, and discuss the diagnostic use of natriuretic peptides as well as various therapeutic agents. By Mark Sutter, MD, and Deborah B. Diercks, MD, FACEP

Heart failure is a disease that has reached epidemic proportions in the United States. There are approximately 550,000 new cases diagnosed every year in this country, bringing the prevalence of the disease to more than 4.5 million patients. The epidemiology of heart failure demonstrates a correlation with age; the incidence in persons over the age of 65 is 10 per 1000. These numbers are staggering, and they are expected to increase as the population ages.

The complexity of heart failure is challenging. Poorly controlled diabetes, hypertension, and dyslipidemias are often found in patients with heart failure. In addition, the number of patients with a previous myocardial infarction and renal disease is increasing. All of these conditions are risk factors for impaired systolic function and predispose patients to heart failure.

As the prevalence of heart failure increases, so does the financial burden associated with the treatment of patients with this disease. It should be our goal to initiate appropriate aggressive therapy for these patients and avoid unnecessary hospitalization. To improve our ability to best utilize our resources, it is necessary to better understand the pathogenesis and treatment of heart failure.

INCREASED UNDERSTANDING

Over the last 10 years, our understanding of heart failure at the molecular and hormonal level has greatly increased. Everyone will agree that the final outcome is the heart's inability to adequately pump blood, but our new understanding of the neurohormonal cascade will help guide therapy.

Traditionally, heart failure has been classified as systolic dysfunction (decreased contractility) and diastolic dysfunction (increased resistance to diastolic filling). The foundation to the pathophysiology of heart failure is based on numerous studies demonstrating ventricular remodeling as a result of the activation of neurohormonal pathways. These pathways include the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS).

The neurohormonal model of heart failure is based on a precipitating event, which puts increased stress on the heart, activating many inflammatory cytokines and neurohormones. These mediators cause a structural change in the ventricular wall that decreases left ventricular function, leading to the clinical syndrome of heart failure (see table).

The Development of Heart Failure

Precipitating event Structural change Syndrome of failure

cardiac causes

-acute coronary syndrome

-valvular disease

-arrhythmias

acute inflammation

hypertension

extracardiac illness

medication noncompliance

dietary noncompliance

endothelial dysfunction

myocyte hypertrophy

ventricular fibrosis

cell necrosis

sodium retention

leg edema

pulmonary congestion

Heart failure leads to a drop in cardiac output, which results in decreased renal perfusion. In response, the body activates the RAAS. The kidneys release the hormone renin and trigger a downstream cascade. Renin will act on circulating angiotensinogen and convert it to angiotensin I. The vascular endothelium responds by releasing angiotensin-converting enzyme (ACE), which converts angiotensin I to angiotensin II. This protein acts as a potent vasoconstrictor, thus increasing renal blood flow.

Angiotensin II also has a direct pathologic effect in the vessel wall, inducing oxidative stress that causes injury to the vessel. These oxidative stressors and vessel injury trigger further immunologic damage. This contributes to the vascular remodeling that leads to heart failure.

In addition, angiotensin II stimulates the adrenal glands to release aldosterone. This promotes increased absorption of sodium in exchange for potassium in the renal tubules, which increases total body fluid volume. Aldosterone also reduces nitric oxide release and promotes endothelial dysfunction; it has also been implicated in increasing myocardial hypertrophy, fibrosis, and necrosis. These effects all lead to stiffness of the ventricles and vasculature, worsening left ventricular function. This pathologic sequence illustrates how activation of the RAAS as a result of decreased renal blood flow actually exacerbates heart failure by promoting salt retention and ventricular remodeling.

AUGMENTED EFFECTS

The effects of the RAAS are augmented by the SNS. As the heart is stressed, the SNS is activated, releasing norepinephrine and other hormones. These work in a variety of ways to exacerbate heart failure. They include direct myocardial toxicity, heightened myocardial demand, increased salt and water retention, peripheral vasoconstriction, and apoptosis. This combination of effects not only can worsen heart failure but can also lead to life-threatening arrhythmias.

The RAAS and SNS are not the only compensatory mechanisms activated when stress is placed on the heart. The ventricles will release B-type natriuretic peptides (BNPs) that cause the efferent renal arteries to constrict and the afferent arteries to dilate. This promotes diuresis and sodium excretion, which will decrease total body fluid volume and help off-load the work placed on the heart.

In addition to their effects on the renal vasculature, the natriuretic peptides have other beneficial properties. They are known to decrease circulating endothelin, a potent vasoconstrictor, and the production of renin and aldosterone.

These complex biochemical chains of events that occur when the heart is stressed seemingly counteract one another. However, the natriuretic system is not as powerful as the RAAS and SNS combined. The balance is tipped toward sodium retention, volume preservation, and increased vascular tone. This neurohormonal pathway contributes to the development of heart failure in patients with both systolic and diastolic dysfunction. In patients with diastolic dysfunction, neurohormonal activation contributes to the progression of the disease by increasing blood pressure and impairing relaxation through myocardial fibrosis and worsening left ventricular hypertrophy.

PATIENT EVALUATION

A definitive diagnosis of heart failure is normally made using modalities not readily available in an emergency department, such as right heart catheterization and echocardiography. This has led to the diagnosis and treatment of heart failure as a uniform entity without regard to etiology or systolic function in the emergency department. Nevertheless, the emergency physician should use the available resources to diagnose heart failure. This usually includes a history, physical examination, ECG, chest radiograph, and laboratory evaluation.

Patients often give a history of nonspecific symptoms, but most do complain of some degree of shortness of breath. Dyspnea, in fact, is the most common symptom in patients presenting with heart failure, but it is also a predominant symptom in other diseases (see box). It is important to take a thorough history to not only evaluate for other causes of heart failure, but also to evaluate for arrhythmias and acute coronary syndrome. These can often be present with heart failure and can be immediately life-threatening. Classic historical complaints such as paroxysmal nocturnal dyspnea and orthopnea are specific for heart failure but not sensitive.

Differential Diagnosis of Dyspnea

• acute coronary syndrome

• aortic dissection

• pulmonary embolism

• valvular dysfunction

• esophageal perforation

• chronic obstructive pulmonary disease

• pneumonia

• bronchitis

• anemia

• sepsis

• obesity

• trauma

• pneumothorax

• vasculitis

• autoimmune disorders

Other symptoms such as fatigue, weakness, and leg swelling often indicate elevated filling pressures, but they can also be due to other causes such as venous insufficiency, right heart failure, or pelvic vein obstruction. Despite the nonspecific constellation of symptoms, perhaps the most indicative historical finding is a prior history of heart failure.

Electrocardiograms are routine in the evaluation of patients with dyspnea and a suspected diagnosis of heart failure. While an ECG may be of limited use in diagnosing heart failure, it can help to identify a precipitating event such as ischemia, infarct, or arrhythmias.

Chest radiography can be an important source of information in the evaluation of a patient for heart failure. The major findings on chest x-ray include cardiomegaly, vascular redistribution (cephalization), and interstitial edema. While these are common, they have not been shown to be sensitive. About 20% of cardiomegaly confirmed by echocardiography is missed on chest radiographs. Studies have also shown that agreement among clinicians in chest x-ray interpretation is "moderate to almost perfect" for interstitial edema, but only "moderate" for cardiomegaly and vascular redistribution. Patients with chronic heart failure are also known to have increased lymphatic drainage; in such cases, radiographs might underestimate the degree of heart failure present.

TOOL OF THE FUTURE

The diagnostic tool of the future for heart failure seems to be the evaluation of natriuretic peptides. Two peptides have moved into the forefront in the diagnosis of heart failure in patients presenting to the emergency department: the BNPs and the N-terminal pro-BNP (NBNP). In response to ventricular wall stretch, both of these peptides are released.

B-type natriuretic peptides have been evaluated in several studies demonstrating their usefulness in diagnosing heart failure in patients with undifferentiated dyspnea. The Breathing Not Properly study showed that BNP levels greater than 100 pg/ml were more accurate than clinical judgment and Framingham criteria in differentiating heart failure from other causes of dyspnea. The odds ratio for BNP of 29.6 was the strongest predictor of heart failure, far superior to any of the physical exam findings. Jugular venous distension had an odds ratio of 1.87; for lower extremity edema, it was 2.88.

It is important to recognize that there are confounders that can cause an elevated BNP level. These occur in conditions that are known to cause elevated right ventricular pressures. Examples of such conditions include pulmonary embolism, fluid overload states such as dialysis and cirrhosis, primary pulmonary hypertension, and possibly even hormone replacement therapy. These conditions can cause BNP levels to rise to the 100 to 500 pg/ml range. Also, in obese patients, the BNP level has been shown to be lower than in nonobese patients, which may decrease its diagnostic utility in those patients.

Recent studies suggest that BNP levels can also be used for risk stratification. One study suggests that a BNP level above 350 pg/dl at the time of hospital discharge is an independent marker of death or readmission, and it is considered more relevant than clinical or echocardiographic parameters and the percentage change in BNP levels during the patient's hospitalization.

N-terminal Pro-BNP is a biologic inert product of BNP synthesis that is believed to be a future marker in the diagnosis of heart failure. Its utility has been evaluated and shown to be useful in the dyspneic patient. Although this marker has not been as extensively evaluated as BNP, it has some useful properties. Unlike with BNP, NBNP values can be used clinically when the patient is being treated with natriuretic peptides. In patients with decompensated heart failure, NBNP levels will be more elevated than BNP and will have a longer half-life. This may alter their utility in the acute setting. Although there are many clinical studies evaluating the use of NBNP, there are no studies that compare NBNP levels with the clinical diagnosis.

MANAGEMENT OF HEART FAILURE

The management goal for all patients with heart failure is to decrease afterload and ventricular wall stretch in an attempt to limit the neurohormonal cascade. To meet this goal, physicians can use nonpharmacologic options such as bilevel positive airway pressure (BiPAP) and mechanical ventilation for critically ill patients in combination with pharmacologic agents. These include inotropic drugs, arterial and venous vasodilators, diuretics, morphine, and natriuretics.

Inotropic drugs. The most commonly used inotropes in heart failure are dobutamine, dopamine, and milrinone. Dobutamine is a catecholamine that acts directly on the beta-1 receptor, causing both a chronotropic and an inotropic response from the heart. Dopamine is also a catecholamine that increases both the chronotropic and inotropic responses of the heart. In addition to its beta-1 actions, dopamine also works on both alpha and dopaminergic receptors. Milrinone is a phosphodiesterase inhibitor that allows for more cyclic adenosine monophosphate to remain in the cell. This results in increased calcium levels and increased contractility.

Inotropes, while effective in increasing contractility in the short term, have been found to have their negative side effects. All of the inotropes can induce arrhythmias, tachycardias, and activate the RAAS; they are also associated with increased mortality. Dobutamine is associated with peripheral vasodilation and tachyphylaxis. Dopamine will induce alpha effects as the dose is increased, thus placing more strain on the heart. Milrinone has been shown to have increased adverse effects and is associated with prolonged hospitalizations.

Arterial and venous dilators. These drugs work to decrease the afterload and preload placed on the heart. Commonly used medications in this category for heart failure are nitroglycerin, nitroprusside, and the ACE inhibitors. Nitroglycerin works to relax smooth muscle by increasing cyclic guanosine monophosphate, which dephosphorylates myosin, leading to vascular relaxation. It has almost no effects on cardiac and skeletal muscle; it works primarily on the venous system. Nitroglycerin will cause venous dilation, resulting in increased venous capacitance and decreased preload. Nitroglycerin is associated with tachycardia, tachyphylaxis, and neurohormonal activation.

Nitroprusside has basically the same mechanism of action as nitroglycerin, but it has dramatic effects on both the arterial and venous systems. Nitroprusside can significantly decrease blood pressure by reducing afterload, but it can be effective in lowering preload as well. Prolonged use of nitroprusside can lead to an accumulation of cyanide. Data from a multicenter heart failure registry reported in the ADHERE trial suggested that patients treated with any intravenous (IV) vasodilator in the emergency department, versus later in their hospital stay or not at all, had lower mortality and shorter hospital stays.

The ACE inhibitors have also been used in the treatment of acute heart failure. They work by blocking the formation of angiotensin II, thereby stopping the effects of its vasoconstrictive properties and thus decreasing afterload. A randomized, double-blind study using IV enalapril in acute pulmonary edema found it to be both effective and well tolerated. Enalapril decreased not only systemic blood pressure but also pulmonary capillary wedge pressure.

Hamilton and colleagues demonstrated in a randomized, prospective, placebo-controlled study that sublingual captopril decreased respiratory distress and produced more rapid clinical improvement when added to standard therapy with nitrates, morphine, oxygen, and furosemide compared to standard therapy alone.

Diuretics. The purpose behind using diuretics in heart failure is to decrease pulmonary congestion and leg edema. Diuretics decrease plasma volume and sodium retention, which subsequently decreases venous return to the heart. This occurs through the induction of diuresis in the kidneys, resulting in a redistribution of fluid and further reduction in fluid overload and a decrease in vascular resistance. It is the vasodilatory effect of the loop diuretics that has the greatest initial impact in symptom reduction in acute decompensation.

In heart failure, loop diuretics such as furosemide are commonly used. The starting dose for furosemide is usually 40 mg or the patient's prehospitalization daily dose, given intravenously. Peak diuretic effects occur 30 to 60 minutes after IV administration. If the patient fails to respond, the common practice is to double the initial dose. Doses higher than 160 to 320 mg should be avoided because side effects, such as electrolyte abnormalities, volume depletion, and activation of the RAAS, are more likely.

If the patient is diuretic-resistant, an alternative approach would be to use a more potent loop diuretic. Torasemide and bumetanide, for example, are reasonable options when furosemide is ineffective. Bumetanide is reportedly 40 to 50 times more potent than furosemide on a milligram-for-milligram basis. If one is still unable to achieve the desired diuresis with these more potent loop diuretics, metolazone can be added. Metolazone is a thiazide-type diuretic that is often administered in conjunction with loop diuretics. Thiazide diuretics must be used cautiously to avoid electrolyte abnormalities and overdiuresis.

There are various options for delivering loop diuretics. The most commonly used routes are oral and IV bolus doses, but continuous infusion of loop diuretics is also effective. It has been shown that a continuous infusion of a diuretic is more effective and less toxic than bolus dosing in the treatment of heart failure in patients with renal insufficiency.

Morphine. Morphine has been used for decades in the treatment of heart failure. It appears to improve symptoms by reducing anxiety and venodilation. Unfortunately, there is little clinical evidence on the effect of morphine on mortality and morbidity in patients with acute heart failure exacerbation. A pre-hospital trial of morphine in patients with acute pulmonary edema found no benefit in the use of morphine in these patients. Another trial reported that the use of morphine was associated with an increased risk of ICU admission.

Natriuretics. The newest pharmacologic agents in the treatment of heart failure are the natriuretics. In 2001, the Food and Drug Administration approved the use of nesiritide for the treatment of acutely decompensated heart failure. Nesiritide is a BNP that acts as an endogenous natriuretic, causing renal vascular changes that promote diuresis. This medication has the potential to tip the balance of power away from the RAAS and SNS and push it toward natriuresis.

Nesiritide has been shown to produce early symptomatic relief and a reduction in pulmonary capillary wedge pressures within 15 minutes. Its effects peak at 30 to 60 minutes. Another advantage is that because it has no effect on heart rate, it does not increase myocardial oxygen consumption. This can be an important advantage with a patient who is acutely decompensated.

Nesiritide does require adjustments in the use of other drugs. Loop diuretics can be used, but the dose must be decreased because nesiritide itself produces a mild to moderate diuresis. Also, ACE inhibitors and other antihypertensives should be withheld for the first hour, until nesiritide's effects have been observed. It is not recommended at this time to combine IV nitroglycerin and nesiritide because of the lack of data on this combination.

In the PROACTION study, 237 patients in an emergency department observation unit who had decompensated heart failure were randomized to standard therapy or at least 12 hours of IV nesiritide. The study results showed that in the nesiritide group there was an 11% decrease in the need for hospital admission from the observation unit, a 21% decrease in heart failure readmission, and a 29% decrease in readmission for patients with New York Heart class III and IV disease. Of note, these differences did not reach statistical significance due to the low number of patients in the study. The two major disadvantages with nesiritide are the cost and the lack of large clinical trials. Head-to-head comparison trials are not complete, and there are questions regarding the renal impact of nesiritide. As further research is conducted, we will learn if the efficacy of nesiritide will compensate for its cost.

APPLYING THE THERAPEUTIC OPTIONS

Having discussed the therapeutic options, we will now review their application to individual patients. If the patient is in obvious respiratory distress or imminent respiratory failure, the patient should be mechanically ventilated, either via Bi-PAP or endotracheally, along with aggressive blood pressure management. If the blood pressure is elevated, nitroglycerin or nitroprusside is an option, with hemodynamic monitoring and ICU admission. If there is cardiogenic shock or symptomatic hypotension, the use of an inotrope such as dobutamine, dopamine, or milrinone is appropriate, with hemodynamic monitoring and ICU admission. This group of patients needs immediate attention, often before the underlying cause of their symptoms is known. Once additional data are gathered from the history and laboratory results, more targeted therapy can be initiated.

If the patient does not fall into the critically ill category, a thorough workup and appropriate diagnostic tests should be performed. Once the diagnosis of heart failure is clear, an attempt should be made to classify the patient as being in high-, medium-, or low- severity heart failure. Studies indicate that approximately 10% of heart failure patients will be in the high-severity group, another 10% in the low-severity group, and the remaining 80% in the medium-severity group.

High-severity patients are usually the ones that will end up in the ICU or at least a telemetry unit. Recommendations for this group include oxygen, a loop diuretic, and nitroglycerin or nitroprusside. Nesiritide can also be used in this group.

Patients in the moderate-severity group often require a floor or telemetry bed, but an observation unit, if available, is a viable option. Treatment usually includes oxygen, a loop diuretic, and nitrates. Aggressive therapy with nesiritide may help limit hospitalizations and keep more patients on observation status. As more studies become available, this option might turn out to be more financially advantageous if lengths of stay can be shortened.

Low-severity patients should receive oxygen, nitrates, and a trial of loop diuretics. A period of observation in the emergency department will usually demonstrate diuresis and symptomatic relief. The physician should use this time for patient education; in many cases, the precipitating event will be something as simple as medication noncompliance or dietary indiscretion. These patients are usually discharged.

NEW REGIMENS

Improved understanding of the pathophysiology in heart failure may lead to the development of new therapeutic regimens. Currently, tezosentan, an endothelin-1 antagonist, is being investigated in the treatment of decompensated heart failure. Initial trials of this drug, however, have not been encouraging. Tolvaptan, a vasopressin antagonist, has also been evaluated in the treatment of decompensated heart failure. Initial studies have shown it to provide added value to diuretics.

Another group of medications used in the management of heart failure is the aldosterone antagonists. While they are not commonly used in the management of an acutely decompensated heart failure patient, they are often included in the outpatient regimen. Spironolactone is in this class of medications. It works by preventing sodium reabsorption, leading to retention of potassium. These drugs also have a very mild diuretic effect. Eplerenone is the newest aldosterone antagonist; it has more selectivity than spironolactone and causes less gynecomastia and progesterone stimulation. Its effects on electrolyte balance appear to be the same as spironolactone's in early studies.

A major risk with patients on aldosterone antagonists is hyperkalemia. A potential problem with spironolactone, which is recommended in severe heart failure, is that patients in that category are usually also on an ACE inhibitor. If the patient has a episode of decompensation, the combination of an ACE inhibitor and an aldosterone antagonist can lead to the deadly complications of hyperkalemia. A recent study in the New England Journal of Medicine showed that since the RALES trial demonstrated a benefit to adding spironolactone to an ACE inhibitor in patients with severe heart failure, the rates of both hospitalization and mortality due to hyperkalemia have increased significantly.

DISPOSITION OF PATIENTS

Depending on institutional policies, new-onset heart failure patients and patients diagnosed with heart failure for the first time usually are admitted to the hospital or undergo echocardiographic evaluation prior to discharge. Echocardiography can not only confirm the diagnosis of heart failure, but it can also help identify systolic or diastolic dysfunction and aid in future treatment plans. Depending on the suspected etiology of new-onset heart failure, additional diagnostic tests to evaluate for underlying coronary artery disease may be performed.

Risk Findings in Heart Failure

High risk

new-onset heart failure

ischemic changes on ECG

low serum sodium

increased respiratory rate

low systolic blood pressure

age >70

chest pain

elevated creatinine

poor diuresis after four hours

pulmonary edema on chest x-ray

severe comorbidities

electrolyte abnormalities

syncope

valvular disease

hemoglobin <10 mg/dl

Low risk

Absence of high-risk features

Normal vital signs and symptomatic improvement after treatment

Good support system and outpatient follow-up

Normal laboratory parameters (electrolytes, cardiac markers)

Possible risk-related considerations in the disposition of patients with heart failure are summarized in the table above. Appropriate discharge from the emergency department must be combined with adequate follow-up. Instruction on diet recommendations, medication schedules, and the importance of tracking body weight are important in preventing readmission.

Suggested Reading

Badgett RG, et al.: Can the clinical examination diagnose left-sided heart failure in adults? JAMA 277(21):1712, 1997.

Bussmann WD and Schupp D: Effect of sublingual nitroglycerin in emergency treatment of severe pulmonary edema. Am J Cardiol 41(5):931, 1978.

DiDomenico RJ, et al.: Guidelines for acute decompensated heart failure treatment. Ann Pharmacother 38(4):649, 2004.

Krum H and Gilbert RE: Demographics and concomitant disorders in heart failure. Lancet 362(9378):147, 2003.

Lee DS, et al.: Predicting mortality among patients hospitalized for heart failure: derivation and validation of a clinical model. JAMA 290(19):2581, 2003.

evy D, et al.: Long-term trends in the incidence of and survival with heart failure. N Engl J Med 347(18):1397, 2002.

Maisel AS, et al.: Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 347(3):161, 2002.

Peacock WF and Emerman CE: Safety and efficacy of nesiritide in the treatment of decompensated heart failure in observation patients. J Am Coll Cardiol 41(suppl A):336A, 2003.

Publication Committee for the VMAC Investigators: Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA 287(12):1531, 2002.

Schrier RW and Abraham WT: Hormones and hemodynamics in heart failure. N Engl J Med 341(8):577, 1999

Hope this helps,

Ace844

[Guest]

Awesome read, thankyou so much.. I'm printing this one out.

[Ace844]

Hi All,

I got very little response from my first post, but I decided to follow it up with another and see if that helps some...So here's the next teaching post in the "Heart Failure" realm... There's also a link here to some great powerpoint slides...

Hope this helps,

Ace844

ACC/AHA 2005 Guideline Update for the Diagnosis andManagement of Chronic Heart Failure in theAdult—Summary Article.

Heart Failure Powerpoint @ info...

Evidence based treatment guidelines... CHF

Diagnosis and Treatment of Diastolic Heart Failure

HOWARD D. WEINBERGER

University of Colorado

Up to 40% of patients with heart failure have isolated diastolic dysfunction. With proper management, the prognosis is generally more favorable than in systolic dysfunction. Distinguishing diastolic from systolic dysfuntion is essential since the optimal therapy for one condition may aggravate the other. New echocardiographic methods enable accurate diagnoses.

For patients older than 65, heart failure is the leading reason for hospitalization in the United States. It is also the most expensive condition to treat. In 1991, for example, hospitalization costs were greater for heart failure than for myocardial infarction and all forms of cancer combined. The total cost of treatment, including inpatient, outpatient, and pharmacy costs, is now estimated to exceed $52 billion a year.

Classically, heart failure has been almost synonymous with left ventricular systolic failure (pump failure). In the last 10 to 20 years, however, it has become apparent that in nearly 40% of cases, systole is normal and diastole abnormal. In 31 studies of heart failure published between 1970 and 1995, the prevalence of isolated diastolic dysfunction ranged from 13% to 74%.

Two of the studies suggest that the condition is age-related. The average incidence was 8% for subjects younger than 65 and 32% for those older than 65. As the population of the United States continues to age, the proportion of heart failure cases due to isolated diastolic dysfunction seems destined to increase.

Physiology of Diastole

The cycle of myocardial contraction and relaxation is directly related to cytosolic calcium concentration. With electrical depolarization, calcium enters the myocyte via slow (L-type) calcium channels. This triggers the release of massive amounts of additional calcium stored in the sarcoplasmic reticulum. The calcium diffuses into the sarcomere, causing a conformational change in the troponin-tropomyosin complex that permits myosin to interact with actin and the myocyte to contract. For the myocyte to relax, the process must be quickly reversed. Up to 90% of the calcium is actively removed by the calcium-ATPase pump in the sarcoplasmic reticulum and the rest by sodium-calcium exchange and other mechanisms (Figure 1). Working against a 10,000-fold concentration gradient requires a high expenditure of energy--one molecule of ATP is consumed for every two molecules of calcium removed by the calcium-ATPase pump.

The relaxation part of the cardiac cycle is subdivided into four phases: 1) isovolumic relaxation, 2) rapid filling, 3) slow filling (diastasis), and 4) atrial contraction (Figure 2). In the first phase, between the time of aortic valve closing and mitral valve opening, calcium is rapidly removed from the cytoplasm and resequestered in the sarcoplasmic reticulum. The next phase begins when pressure in the left ventricle falls below that in the left atrium, causing the mitral valve to open and the left ventricle to begin filling; it ends when pressure in the two chambers is equalized. Although this rapid-filling phase comprises only about 30% of diastole, it accounts for up to 80% of left ventricular volume. The third phase is the slow-filling phase. What little filling there is comes from pulmonary vein flow. With increased heart rate, this phase shortens more than the other three. The fourth phase, atrial contraction, contributes 15% to 25% of the left ventricular volume under normal conditions but can contribute as much as 40% if left ventricular relaxation is diminished.

D.L. Brutsaert and colleagues consider the first two phases to be the end of systole. By their definition, diastole would consist of phases 3 and 4. It would thus comprise about 50% of the cardiac cycle but at normal heart rates would contribute only the last 5% to 15% of the ventricular volume.

Etiology of Diastolic Dysfunction

In 1991, Kitzman and colleagues demonstrated that pulmonary venous pressure, and hence left ventricular filling pressure, is elevated at rest in patients with isolated diastolic dysfunction. With exercise, the filling pressure further increases, but the left ventricular volume decreases (Figure 3). Even higher filling pressures would be required to fill the left ventricle and maintain normal cardiac output.

Diastolic heart failure is an insidious disease. Insults to the myocardium are followed by a series of compensatory changes that are beneficial in the short run but have long-term deleterious effects. Structural remodeling and other factors, including myocardial ischemia, left ventricular hypertrophy, increased heart rate, and abnormal calcium flux, can impair diastolic function and cause an increase in left ventricular filling pressures (Table 1).

Table 1. Factors Increasing Diastolic Pressure

Impaired Ventricular Relaxation

--------------------------------------------------------------------------------

Hypertrophy

Myocardial ischemia

Hypertension

Collagen deposition and fibrosis

Regional asynchrony

Increased preload, afterload

Abnormal calcium flux

Tachycardia Decreased Ventricular Compliance

--------------------------------------------------------------------------------

Hypertrophy

Hypertension

Collagen deposition and fibrosis

Cellular disarray

Myocardial infiltration

Pericardial constriction or restriction

Right ventricle-left ventricle interactions

Both ischemia and hypertrophy impair relaxation in early diastole--ischemia by restricting the supply of high-energy phosphates required for rapid removal of calcium from the cytoplasm and hypertrophy by slowing the rate of myosin-actin dissociation. Hypertrophy also decreases left ventricular compliance in all phases of diastole.

The probability of ischemia or left ventricular hypertrophy increases with age. Additional correlates of aging, such as hypertension and increased interstitial collagen deposition, result in decreased left ventricular compliance. It is thus not surprising that old age is among the most frequently cited risk factors for isolated diastolic dysfunction.

Other leading causes of the condition are coronary artery disease, hypertension, diabetes, obesity, and aortic stenosis (Table 2). Up to 90% of patients with coronary artery disease have abnormal diastolic function, and approximately 60% of patients with heart failure and normal systolic function have hypertension. Obese patients, with or without hypertension also have an increased risk of heart failure due to diastolic dysfunction.

Table 2. Causes of Isolated Diastolic Dysfunction

Common

--------------------------------------------------------------------------------

Coronary artery disease

Hypertension

Aging

Diabetes mellitus

Obesity

Aortic stenosis

Less Common

--------------------------------------------------------------------------------

Hypertrophic cardiomyopathy

Infiltrative cardiomyopathies

Endocardial fibroelastosis

Pericardial disease

Diagnosis

It is important to distinguish between systolic and isolated diastolic dysfunction since the treatment for one condition may aggravate or worsen the other. Unfortunately, the classic manifestations of heart failure are not helpful in this regard. Studies conducted by H. H. Echeverria and colleagues demonstrated that eight of the most common signs and symptoms of heart failure are present with nearly equal frequency in systolic and diastolic dysfunction (Figure 4).

The diagnostic workup must not only confirm signs and symptoms of heart failure but include an assessment of systolic as well as diastolic function. Valvular, pericardial, and pulmonary function must also be evaluated. The methods used most frequently are two-dimensional echocardiography, Doppler echocardiography, and radionuclide ventriculography.

Two-dimensional echocardiography provides the necessary structural and functional information on chamber size, wall thickness and motion, systolic function, intracardiac valves, and the pericardium. Additional information on blood flow, valvular stenosis, regurgitation, and intracardiac pressures is obtained by Doppler echocardiography. Doppler measurements also allow estimates of right atrial pressure, right ventricular systolic pressure, and pulmonary artery systolic pressure. The relative velocities of blood flow into the left ventricle in the rapid-filling and atrial contraction phases of diastole allow an assessment of left ventricular relaxation and compliance. Similarly, the pattern of pulmonary vein flow allows an estimation of left ventricular end-diastolic pressure and left atrial pressure.

A quantitative left ventricular ejection fraction can be obtained by radionuclide ventriculography (gated blood-pool scanning). With the proper equipment, the peak filling rate and time to peak filling can also be obtained. The left ventricular volume, and perhaps the thickness of the chamber wall, can be estimated, but the methodology does not permit direct visualization of cardiac chambers, walls, valves, or pericardium. Nor does it allow evaluation of intracardiac pressures.

For these reasons, echocardiography is the best noninvasive means of evaluating left ventricular diastolic function. Tissue Doppler echocardiography of the mitral annulus and color M-mode echocardiography have been recently validated in clinical trials. The assessments obtained by these techniques were in excellent agreement with invasive measurements. Those obtained by tissue Doppler echocardiography appeared to be relatively preload-independent and thus particularly useful for evaluating isolated diastolic dysfunction.

Treatment

Numerous agents have been shown to be beneficial for treatment of systolic heart failure, but the efficacy of these or other agents for treatment of isolated diastolic failure has not been adequately tested. The underlying or aggravating causes of isolated diastolic failure, as well as the abnormalities produced, may require drugs with different mechanisms of action. As in any disease, the treatment should be as specifically directed as possible (Table 3).

Table 3. Goals in Treating Isolated Diastolic Heart Failure

Resolve causative or aggravating factors

Enhance left ventricular relaxation if necessary

Decrease left ventricular filling pressure without decreasing cardiac output

Slow heart rate if too rapid

Control ventricular rate if atrial fibrillation is present

Maintain atrial-ventricular synchrony

Maintain sinus rhythm

Prevent excess contractility

Isolated diastolic heart failure is currently treated with calcium channel blockers (mainly verapamil and diltiazem), beta-adrenergic receptor blockers, or angio-tensin-converting enzyme (ACE) inhibitors. In cases of pulmonary congestion or ischemia, patients may also receive diuretics or nitrates, respectively.

Calcium channel antagonists can improve diastolic function directly, by attenuating calcium homeostasis, or indirectly, by reducing blood pressure, reducing or preventing myocardial ischemia, promoting regression of left ventricular hypertrophy, slowing heart rate (verapamil, diltiazem), and improving left ventricular filling parameters.

Thus far, verapamil is the only drug shown by objective criteria to improve diastolic function, ameliorate symptoms, and increase exercise tolerance. In a five-week, double-blind cross-over trial conducted in 1990 by J.F. Setaro and colleagues, 20 elderly men with isolated diastolic dysfunction were treated with verapamil or placebo. In those receiving the drug, symptoms improved, exercise time increased 33%, peak left ventricular filling rate increased 30%, and heart rate decreased 10% (p<.05 for all).

Table 4. Therapies for Isolated Diastolic Dysfunction

Calcium

channel

blocker Beta-adrenergic

receptor ACE inhibitor Diuretic Nitrate

Enhances myocardial relaxation + ­ ? ­ ­

Reduces blood pressure + + + + ­

Reduces or prevents ischemia + + ­ ­ +

Promotes regression of left ventricular hypertrophy ++ + ++ + ­

Slows heart rate + + ­ ­ ­

Reduces collagen deposition and fibrosis ­ ­ + ­ ­

Improves left ventricular filling parameters + ? + ? ?

Improves symptoms + ? + +* ?

? = no studies, * = pulmonary congestion

Beta-adrenergic receptor blockers have no direct effect on myocardial relaxation but have proven benefits in reducing blood pressure, reducing or preventing myocardial ischemia, promoting regression of left ventricular hypertrophy, and slowing heart rate. ACE inhibitors, on the other hand, may directly affect myocardial relaxation and compliance by inhibiting production of angiotensin II, which is known to be involved in interstitial collagen deposition and fibrosis. The indirect benefits of ACE inhibitors include reducing blood pressure, improving left ventricular filling parameters, and promoting regression of left ventricular hypertrophy.

Positive inotropic or chronotropic agents (e.g., digoxin or dobutamine), potent arterial vasodilators (hydralazine), and alpha-adrenergic receptor blockers (prazosin) should be avoided. In the absence of systolic dysfunction, they are likely to worsen diastolic function by increasing contractile force or heart rate. Diuretics and nitrates may be used in certain cases, but it is important to realize that if abnormally high pressure is required to fill the left ventricle, decreasing the preload can worsen cardiac output.

Prognosis

The annual mortality of patients with isolated diastolic heart failure appears to be three- to fourfold lower on average than that of patients with systolic heart failure. The figures reported for isolated diastolic failure (1.3%-17.5%), however, are more variable than for systolic failure (15%-20%). This may relate to differences in the age of the subjects, the prevalence of coronary artery disease or left ventricular hypertrophy in the study cohort, or the treatment received.

In the Vasodilator in Heart Failure Trial I (V-HeFT I), for example, the annual mortality for patients with a normal left ventricular ejection fraction was less than half that of patients with a reduced left ventricular ejection fraction (8% vs. 19%, p=.0001; Figure 5). The difference might have been even greater had not all of the patients been treated with preload or afterload reducing agents (nitrates; hydralazine, prazosin) that could have worsened diastolic function.

Coronary artery disease, hypertension, and a number of other conditions may cause systolic as well as diastolic heart failure. In such cases, diastolic dysfunction precedes systolic dysfunction. Unless the underlying cause of heart failure is identified and adequately controlled, the patient's condition will progressively worsen.

Summary

Congestive heart failure is a major contributor to morbidity, mortality, hospitalization, and medical costs in the United States. Up to 40% of cases are due to isolated diastolic dysfunction, most of which result from coronary artery disease, hypertension, aging, diabetes mellitus, obesity, or aortic stenosis.

Isolated diastolic heart failure cannot be reliably diagnosed by history and physical examination alone. It is imperative to make an accurate diagnosis since treatments for systolic and diastolic dysfunction differ; what is optimal for one may aggravate or exacerbate the other. Echocardiography is the best means of diagnosing the condition noninvasively.

Treatment for isolated diastolic dysfunction may include the use of calcium channel antagonists, beta-adrenergic receptor blockers, ACE inhibitors, and the careful use of diuretics for pulmonary congestion and nitrates for myocardial ischemia. Positive inotropic or chronotropic agents, potent vasodilators, and alpha-adrenergic receptor blockers should be avoided, since they can worsen diastolic function when systolic function is normal.

HOWARD D. WEINBERGER

University of Colorado::http://www.hosppract.com/issues/1999/03/weinb.htm

Diastolic Dysfunction

Ventricular function is highly dependent upon preload as demonstrated by the Frank-Starling relationship. Therefore, if ventricular filling (preload) is impaired, this will lead to a decrease in stroke volume. The term "diastolic dysfunction" refers to changes in ventricular diastolic properties that have an adverse effect on stroke volume.

Ventricular filling (i.e., end-diastolic volume and hence sarcomere length) depends upon the venous return and the compliance of the ventricle during diastole. A reduction in ventricular compliance, as occurs in ventricular hypertrophy, will result in less ventricular filling (decreased end-diastolic volume) and a greater end-diastolic pressure (and pulmonary capillary wedge pressures) as shown to the right by changes in the ventricular pressure-volume loop. Stroke volume, therefore, will decrease. Depending on the relative change in stroke volume and end-diastolic volume, there may or may not be a small decrease in ejection fraction. Because stroke volume is decreased, there will also be a decrease in ventricular stroke work.

A second mechanism can also contribute to diastolic dysfunction: impaired ventricular relaxation (reduced lusitropy). Near the end of the cycle of excitation-contraction coupling in the myocyte, the sarcoplasmic reticulum actively sequesters Ca++ so that the concentration of Ca++ in the vicinity of troponin-C is reduced allowing the Ca++ to leave its binding sites on the troponin-C and thereby permit disengagement of actin from myosin. This is a necessary step to achieve rapid and complete relaxation of the myocyte. If this mechanism is impaired (e.g., by reduced rate of Ca++ uptake by the sarcoplasmic reticulum), or by other mechanisms that contribute to myocyte relaxation, then the rate and perhaps the extent of relaxation are decreased. This will reduce the rate of ventricular filling, particularly during the phase of rapid filling.

An important and deleterious consequence of diastolic dysfunction is the rise in end-diastolic pressure. If the left ventricle is involved, then left atrial and pulmonary venous pressures will also rise. This can lead to pulmonary congestion and edema. If the right ventricle is in diastolic failure, the increase in end-diastolic pressure will be reflected back into the right atrium and systemic venous vasculature. This can lead to peripheral edema and ascites.

Pulmonary edema

Pulmonary edema is a condition associated with increased loss of fluid from the pulmonary capillaries into the pulmonary interstitium and alveoli. Pulmonary edema of cardiac origin usually results from an increase in pulmonary capillary pressure caused by an elevation of left atrial pressure associated with left ventricular failure or valve disease (e.g., mitral or aortic regurgitation, mitral or aortic stenosis). Pulmonary hypertension can also lead to elevated capillary pressures and pulmonary edema. The physical factors and dynamics of edema formation.

Tissue Edema and General Principles of Transcapillary Fluid Exchange

· General Principles

· Factors Precipitating Edema

· Prevention and Treatment of Edema

Edema refers to the swelling of tissues that result from excessive accumulation of fluid within the tissue. Edema can be highly localized, for example, a small region of the skin subjected to a bee sting. Edema, however, can also comprise an entire limb, specific organs such as the lungs (e.g., pulmonary edema) or the whole body.

General principles

To understand how edema occurs, it is first necessary to explain the concept of tissue compartments. There are two primary fluid compartments in the body between which fluid is exchanged - the intravascular and extravascular compartments. The intravascular compartment contains fluid (i.e., blood) within the cardiac chambers and vascular system of the body. The extravascular system is everything outside of the intravascular compartment. Fluid and electrolytes readily move between these two compartments. The extravascular compartment is made up of many subcompartments such as the cellular, interstitial, and lymphatic subcompartments, and a specialized system containing cerebrospinal fluid.

The movement of fluid and accompanying solutes between compartments (mostly water, electrolytes, and smaller molecular weight solutes) is governed by physical factors such as hydrostatic and oncotic forces. These forces are normally balanced in such a manner the fluid volume remains relatively constant between the compartments. If the physical forces or barriers to fluid movement are altered, the volume of fluid may increase in one compartment and decrease in another. In some cases, total fluid volume increases in the body so that both intravascular and extravascular compartments increase in volume. This can occur, for example, when the kidneys fail to excrete sufficient amounts of sodium and water. When the fluid volume within the interstitial compartment increases, this compartment will increase in size leading to tissue swelling (i.e., edema). When excess fluid accumulates within the peritoneal space, this is termed "ascites." Pulmonary congestion, which can occur in heart failure as the left atrial pressure increases and blood backs up in the pulmonary circuit, causes pulmonary edema.

A model that helps us to understand what causes edema is shown to the right. In most capillary systems of the body, there is a net filtration of fluid from the intravascular to the extravascular compartment. In other words, capillary fluid filtration exceeds reabsorption. This would cause fluid to accumulate within the interstitium if it were not for the lymphatic system that removes excess fluid from the interstitium and returns it back to the intravascular compartment. Circumstances, however, can arise where net capillary filtration exceeds the capacity of the lymphatics to carry away the fluid (i.e., net filtration > lymph flow). When this occurs, the interstitium will swell with fluid, thereby become edematous.

Factors Precipitating Edema

· Increased capillary hydrostatic pressure (as occurs when venous pressures become elevated by gravitational forces, in heart failure or with venous obstruction)

· Decreased plasma oncotic pressure (as occurs with hypoproteinemia)

· Increased capillary permeability caused by proinflammatory mediators (e.g., histamine, bradykinin) or by damage to the structural integrity of capillaries so that they become more "leaky" (as occurs in tissue trauma, burns, and severe inflammation)

· Lymphatic obstruction (as occurs in filariasis)

Prevention and Treatment of Edema

The treatment for edema involves altering one or more of the physical factors that regulate fluid movement. For example, in edema (pulmonary or systemic) secondary to heart failure, diuretics are given to reduce blood volume and venous pressure. If a patient suffers from ankle edema, that person will be instructed to keep their feet elevated whenever possible (to diminish the effects of gravity on capillary pressure), use tight fitting elastic hose (to increase tissue hydrostatic pressure), and possibly be prescribed a diuretic drug to enhance fluid removal by the kidneys.

[Ace844]

Part 2

Diastolic Dysfunction

Diastolic dysfunction is diagnosed in those patients with HF symptoms that are found to have preserved systolic dysfunction and an EF greater than 40%. Some of the disorders associated with diastolic dysfunction include: restrictive cardiomyopathy, obstructive and non-obstructive cardiomyopathy, and infiltrative cardiomyopathies1. With diastolic dysfunction, filling of the ventricles is impeded due to fibrosis and the lack of relaxation. HF is predominately found in elderly women with hypertension 10 .

Making the diagnosis of diastolic dysfunction is often difficult. The diagnosis is generally made by findings on an echocardiogram. These patients that are found to have signs or symptoms of HF with a normal ejection fraction are diagnosed with diastolic dysfunction1. There have been few clinical trials to evaluate the treatments for diastolic dysfunction. Treatment is generally based on physiologic factors such as blood pressure, heart rate, uncontrolled blood volume and ischemia. Hypertension can cause both functional and structural changes in the heart. Both systolic and diastolic blood pressure should be controlled using published guidelines to prevent the development of diastolic dysfunction1. Tachycardia shortens both the ventricular filling time and perfusion of the coronary arteries. Those medications that slow the heart rate can improve symptoms in diastolic dysfunction. Diuretics may also decrease blood volume, thus improving shortness of breath in these patients. If patients are ischemic they should be considered for revascularization to alleviate ischemia and ultimately improve their symptoms.

Improving outcomes in diastolic heart failure

Techniques to evaluate underlying causes and target therapy

Mikhail Torosoff, MD, PhD; Edward F. Philbin, MD

VOL 113 / NO 3 / MARCH 2003 / POSTGRADUATE MEDICINE

This is the second of three articles on heart failure.

Preview: Abnormal diastolic function is a common cause of clinical heart failure, particularly among elderly patients. Through early diagnosis and careful management of diastolic dysfunction, these patients can expect improved functional capacity and, in some cases, a favorable long-term outcome. In this article, Drs Torosoff and Philbin discuss how to confirm the diagnosis of diastolic heart failure through objective testing. Current approaches to the treatment of symptoms, including reduction of intravascular volume, heart rate control, and elimination of precipitating factors, are also presented.

Torosoff M, Philbin EF. Improving outcomes in diastolic heart failure. Postgrad Med 2003;113(3):51-58

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The possible causes of diastolic dysfunction include hypertensive heart disease, left ventricular hypertrophy, acute and chronic coronary artery disease (CAD), aging, and infiltrative cardiomyopathies (eg, amyloidosis, hemochromatosis), thyroid disease, myocardial ischemia, and pericardial disease. In this condition, diminished myocardial relaxation raises filling pressures, lowers cardiac output, and causes pulmonary congestion.

Exercise, tachycardia, anemia, fever, and other systemic stressors may provoke or worsen symptoms in patients with diastolic dysfunction. Although clinical heart failure may be diagnosed at a patient's bedside, diastolic dysfunction is confirmed by objective testing. Two-dimensional and Doppler echocardiographic techniques often are used to evaluate left ventricular structure and patterns of blood flow.

Treatment of diastolic dysfunction includes preventive measures, management of symptoms and, when possible, treatment of underlying causes. In treating symptoms, reduction of intravascular volume, control of heart rate, and elimination of precipitating factors are essential. Patients with diastolic heart failure can anticipate improved functional capacity and perhaps an improved long-term outcome with careful clinical management.

Diastolic properties and dysfunction

Broadly defined, diastolic dysfunction is a change in cardiac properties that impairs the ability of the ventricular cavity to accommodate normal end-diastolic volume at normal filling pressures--either at rest or during exercise (1,2). A slower rate of filling causes elevated diastolic pressure and, in the extreme, diminished cardiac output. The lessened output leads to such symptoms as dyspnea, effort intolerance, and edema. Many factors that interfere with the normal active and passive phases of filling can cause clinically apparent diastolic dysfunction.

Normal diastolic characteristics

Diastole is an active, energy-requiring process in which the heart relaxes immediately after contraction, vigorously filling the ventricular cavity with blood (1,2). Diastole can be divided into four phases: isovolumic relaxation, early passive filling, diastasis, and filling during atrial contraction.

In isovolumic relaxation, intracellular calcium is sequestered in the sarcoplasmic reticulum, deactivating actin-myosin crossbridges. During this phase, vigorous relaxation produces a suction effect that facilitates active early ventricular filling. Ischemia (which reduces the energy supply) or other processes that slow calcium sequestration within the myocyte can prolong the isovolumic relaxation time and impair ventricular filling.

With the opening of the mitral valve, isovolumic relaxation ends and early passive ventricular filling commences. Filling is dependent on the pressure gradient between the left atrium and left ventricle, as well as the viscoelastic properties of the myocardium. Early in the course of diastolic dysfunction, when left ventricular relaxation is slowed but atrial pressure has not yet risen, the gradient is diminished, reducing ventricular filling. During diastasis, pressures in the left atrium and ventricle equilibrate, which results in slowed blood flow across the mitral valve. Finally, with atrial contraction, an active pressure gradient between the left atrium and ventricle is again produced and facilitates late diastolic filling.

Properties of diastolic dysfunction

When diastolic dysfunction is present, late filling must increase in a compensatory fashion to bring ventricular end-diastolic volume to its normal level, and proportionately more ventricular filling is shifted to the later moments of diastole. In severe cases of diastolic dysfunction, the ventricle becomes so stiff that even the atrial muscle fails and normal end-diastolic volume is not achieved, despite elevated filling pressure. This process leads to reduced stroke volume and the clinical manifestations of low cardiac output. Many experts call this final stage restrictive physiology.

Because normal cardiac relaxation requires a rich supply of high-energy compounds, myocardial relaxation is impaired early and significantly in the presence of acute cardiac ischemia. This usually occurs before any systolic dysfunction is apparent (1,2). Therefore, during ordinary angina episodes or in the context of acute coronary syndromes, transient periods of diastolic dysfunction typically are present. On the other end of the spectrum, left ventricular hypertrophy and fibrosis affect the viscoelastic properties of myocardium in a more chronic way, making the myocardium less compliant and predisposing to chronic heart failure.

Considering the prevalence of CAD, hypertension, and left ventricular hypertrophy in the US population, the public health implications of diastolic dysfunction are apparent (3-5). Diastolic dysfunction occurs early in the course of many cardiac diseases and increases in frequency with age. Whereas it is the underlying cause of heart failure in 35% to 45% of cases, diastolic dysfunction accounts for at least 70% of heart failure in patients aged 80 years and older.

Diastolic heart failure

Many patients with clinical heart failure have normal systolic function of the left ventricle when its contractile properties are measured with such laboratory tests as echocardiography or angiography. When this occurs, physicians often suspect abnormal cardiac filling as the cause of a patient's heart failure and call this syndrome diastolic heart failure. However, more precise and accurate use of the term also requires laboratory evidence of abnormal diastolic function (6-8). Diastolic function can be assessed by various commonly available tests, including echocardiography, nuclear left ventriculography, and cardiac catheterization.

Some patients with acute systolic heart failure may experience improvement in ejection fraction either spontaneously or in response to initial treatment. Thus, patients who display normal ejection fraction during testing performed at a time distant from a clinical episode of heart failure may have had transient systolic dysfunction and not diastolic failure. Moreover, patients with acute respiratory insufficiency and normal ejection fraction may have had an acute noncardiac event, such as asthma or pneumonia, and not cardiac failure.

Diastolic dysfunction may be discovered in a previously symptom-free patient during a laboratory test performed for other indications. In fact, some degree of diastolic dysfunction is part of normal aging. Although such patients usually have a truly pathologic ventricular filling pattern, the clinical significance of isolated and asymptomatic diastolic dysfunction is unclear.

By definition, some degree of diastolic dysfunction is usually present when heart failure is caused by systolic dysfunction (low ejection fraction). In such cases, however, the thrust of treatment is on the systolic components of the heart failure syndrome. When severe diastolic failure (restrictive physiology) and severe systolic failure coexist, the patient's prognosis is particularly poor.

With these details in mind, a reasonable definition of diastolic heart failure requires the following:

Presence of symptoms, physical findings, and results of basic laboratory tests (eg, chest radiograph) that are compatible with heart failure

Exclusion of other medical conditions that can masquerade as heart failure, such as asthma and pneumonia

Results of tests of cardiac function performed in close proximity to the clinical episode that show normal left ventricular systolic function but abnormal diastolic function

Evaluation of left ventricular diastolic function

A carefully taken history and physical examination are the first steps to discovering evidence of underlying diastolic dysfunction. Older age, hypertension, and CAD are common clinical risk states (4,5). Rarely, infiltrative diseases that involve the heart, such as amyloidosis or hemochromatosis, are the cause. Both hypothyroidism and hyperthyroidism can cause or precipitate diastolic dysfunction. Orthopnea, dyspnea, exercise intolerance, chest discomfort, palpitations, weight gain, and peripheral edema are common presenting symptoms. In the early stages of diastolic dysfunction, some symptoms may occur only with exertion or physical stress. In its extreme form, diastolic dysfunction may cause such problems as impaired cognitive function and renal dysfunction as manifestations of low cardiac output.

Findings on physical examination are similar in systolic and diastolic heart failure. In fact, neither the physical examination (9) nor the chest radiograph reliably distinguishes between these entities (10). Electrocardiography may show left ventricular hypertrophy due to hypertensive heart disease or other causes. Arrhythmias, particularly atrial fibrillation, may be present and may contribute to the clinical presentation but are not thought to directly cause diastolic dysfunction.

Laboratory tests can greatly aid in confirming the presence and elucidating the cause of diastolic dysfunction. Echocardiography is very useful in the noninvasive evaluation of suspected diastolic dysfunction (6,7). It allows determination of ventricular size, wall thickness, isovolumic relaxation time, and quantitative and qualitative assessment of early and late diastolic filling. Information can also be obtained about pericardial properties and pericardial effusion. Left ventricular wall thickness that exceeds 11 mm in the presence of a normal left ventricular end-diastolic dimension (<55 mm) confirms ventricular hypertrophy. Atrial enlargement is usually found with long-standing diastolic dysfunction. Discrete regional abnormalities of ventricular contraction suggest acute or chronic ischemic injury as a consequence of CAD. Infiltrative cardiomyopathies can cause changes in tissue characteristics of the myocardium, which are detectable by ultrasound. Thickening of the valve leaflets is typically present with amyloidosis but is rare with other infiltrative cardiomyopathies.

Significant information can be gained from interrogation of blood flow between the left atrium and left ventricle at the level of the mitral valve. Because intracardiac blood flow is a function of the pressure gradient between contiguous cardiac chambers and the size of the orifice between them, blood flow velocities can be used to estimate pressure gradients and the changes in these gradients over time and under various conditions. Early ventricular filling correlates with the E wave of the transmitral Doppler flow pattern; late active filling correlates with the A wave (figure 1).

The normal transmitral filling pattern is characterized by a predominant E wave that has a duration (deceleration time) of more than 200 milliseconds. When relaxation is impaired, ventricular pressure falls more slowly than normal, and the early diastolic left atrium-left ventricle pressure gradient decreases. Accordingly, the velocity (height) of the E wave diminishes and typically becomes less than the velocity of the A wave. This pattern reflects the fact that late diastolic filling is more significant under abnormal conditions than it is normally (figure 2).

As diastolic dysfunction progresses over time, absolute left atrial pressure rises and restores the left atrium-left ventricle pressure gradient to its "normal" range. Even though the gradient is normal, absolute pressures in both the ventricle and atrium are supranormal, giving rise to the term pseudonormalization. The Doppler pattern of pseudonormalization is characterized by a tall but abnormally narrow E wave and a deceleration time of less than 140 milliseconds (figure 3). In end-stage diastolic dysfunction, the atrium fails and is unable to generate pressure. Accordingly, the Doppler pattern of late and advanced diastolic dysfunction (restricted) is abnormally low-velocity A waves.

Computed tomography and magnetic resonance imaging can aid in the evaluation of pericardial disease by showing thickening, calcification, and effusion. Nuclear imaging can provide information about ejection fraction, chamber volume, and rate of ventricular filling. This technique is especially useful with large patients or others with difficult acoustic windows that preclude precise echocardiographic imaging. Cardiac catheterization is usually not required to document the physiology of diastolic dysfunction. However, the hemodynamic patterns of diastolic dysfunction are present when such patients undergo catheterization for other reasons, such as the evaluation of coronary disease. Myocardial biopsy can be used to evaluate infiltrative diseases of the heart.

Precipitating causes of heart failure

Most patients with isolated diastolic dysfunction are free of symptoms when at rest or when not faced with such physical stressors as ischemia, exercise, cardiac arrhythmias, infection or inflammation, anemia, thyrotoxicosis, or fever (table 1).

Table 1. Common precipitating factors in diastolic heart failure

Volume overload

Tachycardia

Hypertension

Ischemia

Exercise

Conduction disturbances and arrhythmias

Atrial fibrillation

Atrioventricular nodal block

Intraventricular conduction delays

Systemic stressors

Anemia

Fever

Infection

Inflammation

Thyrotoxicosis

Emotional stress

Pericardial effusion

Withdrawal of effective cardiac medications

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By directly or indirectly impairing ventricular filling or by augmenting venous return, these stressors can exacerbate the physiologic factors of diastolic dysfunction. Regardless of cause, tachycardia often provokes clinical symptoms in patients with underlying diastolic dysfunction. By definition, it reduces the time available for cardiac filling as it trims the last milliseconds from diastole. Normally, most filling occurs in early diastole.

Tachycardia does not compromise cardiac filling in healthy persons. However, among patients with delayed cardiac relaxation, tachycardia can profoundly affect diastolic filling, elevate left atrial pressure, and produce symptoms of heart failure. In patients with tachycardia and loss of atrioventricular synchrony (as occurs with rapid atrial fibrillation), both tachycardia and the loss of synchronized atrioventricular contraction contribute independently to diastolic dysfunction. Under such circumstances, loss of atrioventricular synchrony in and of itself may cause a 20% to 25% decrease in cardiac output.

Exercise presents a physiologic challenge for patients with diastolic dysfunction. During exercise, a healthy person augments cardiac output severalfold by increasing venous return, raising end-diastolic volume, and increasing heart rate. The compliance of the healthy heart allows tachycardia and increased venous return during exercise without a significant rise in ventricular end-diastolic pressure. In contrast, in a patient with diastolic dysfunction, exercise-related tachycardia and increased venous return produce a sharp rise in filling ventricular pressures and place the patient at risk for symptomatic decline (2).

Ischemia causes diastolic dysfunction because depletion of energy-rich compounds impedes the relaxation process. Thus, both acute and chronic ischemic heart disease can cause or exacerbate diastolic dysfunction. The presence of a new third heart sound in a patient with other manifestations of acute ischemic heart disease is often due to diastolic dysfunction.

Treatment

Although there is no specific short-term therapy for the cellular or subcellular abnormalities that cause diastolic dysfunction, a variety of effective treatment measures can be used to ameliorate symptoms of acute and chronic heart failure and prevent exacerbations. Management of diastolic dysfunction also includes prevention of the onset and progression of predisposing conditions.

Successful treatment of diastolic dysfunction involves the definition and management of its origin and underlying mechanism or mechanisms. Primary and secondary prevention of CAD can avert cases of diastolic dysfunction associated with myocardial ischemia. Likewise, aggressive treatment of hypertension with the goal of preventing or reversing left ventricular hypertrophy is beneficial. Treatment of hypertension in elderly patients can reduce the incidence of heart failure significantly (11,12).

The goals of medical treatment of diastolic dysfunction involve optimization of hemodynamic conditions, including cardiac preload and afterload, as well as treatment of symptoms (table 2). Angiotensin-converting enzyme (ACE) inhibitors reduce blood pressure, prevent or reverse left ventricular hypertrophy, reduce preload, and favorably affect vascular and cardiac remodeling. Accordingly, there is a strong rationale for their use in diastolic heart failure. Although preliminary studies suggest that ACE inhibitors benefit patients with diastolic heart failure (5,13), confirmation awaits the completion of large, placebo-controlled randomized mortality trials. Until then, it is reasonable for physicians to prescribe ACE inhibitors when hypertension is linked to diastolic heart failure and perhaps in other cases of diastolic dysfunction as well.

Table 2. Treatment approach to diastolic heart failure

Primary and secondary prevention of diastolic dysfunction

Prevention and treatment of hypertension and other causes of left ventricular hypertrophy

Prevention and treatment of ischemic heart disease

Surgical removal of diseased pericardium for pericardial constraint

Chemotherapy for infiltrative cardiomyopathies

Optimization of circulating volume

Salt and water restriction

Diuresis, dialysis, or plasmapheresis

Use of angiotensin-converting enzyme (ACE) inhibitors

Use of aldosterone antagonists (theoretical benefit)

Management of tachycardia and tachyarrhythmia

Use of beta-adrenergic blockers (preferred)

Use of calcium channel blockers (as second-line agents)

Use of digoxin (Digitek, Lanoxicaps, Lanoxin) (controversial; has produced inconsistent results)

Atrioventricular node ablation when necessary in rare cases

Maintenance of normal sinus rhythm for atrial fibrillation and other arrhythmias

Dual-chamber pacemaker for significant bradycardia

Optimization of neurohormonal milieu

ACE inhibitors

Beta-adrenergic blockers

Aldosterone antagonists

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The hormone aldosterone promotes fibrosis in the heart and thus contributes to diastolic stiffness. The aldosterone antagonist spironolactone has been shown in a preliminary study (14) to reduce myocardial fibrosis and may prove to have a role in the treatment of diastolic heart failure.

Maintenance of optimum intravascular volume is important to minimize dyspnea and avoid episodes of acute heart failure. Volume overload can be prevented or minimized by a low-salt diet, judicious use of diuretics and, if necessary, renal dialysis.

Control of heart rate and prevention of tachycardia are important in patients with diastolic dysfunction. In theory, heart rate control optimizes cardiac filling by maximizing the diastolic filling period. Beta-blockers are particularly useful for this purpose. They prevent tachycardia, lower blood pressure, reverse left ventricular hypertrophy, and antagonize the excessive adrenergic stimulation common in heart failure. Calcium channel blockers also are useful for controlling heart rate and lowering blood pressure. They can be used if beta-blockers are contraindicated (eg, in patients with severe asthma) or when a full-dose beta-blockade inadequately controls heart rate. However, calcium channel blockers have not been proved in large, prospective, randomized controlled trials to reduce mortality in patients with normal ejection fraction and heart failure due to isolated diastolic dysfunction.

Because digoxin (Digitek, Lanoxicaps, Lanoxin) raises intracellular calcium levels, it might be ineffective in the treatment of diastolic heart failure. In fact, a specific subset of patients with diastolic failure--elderly patients with ventricular hypertrophy--appear to do worse with digoxin than without it. However, the Digitalis Investigation Group trial showed clinical benefit of digoxin use in patients with chronic heart failure, normal sinus rhythm, and an ejection fraction of more than 45% (15). Because laboratory confirmation of diastolic dysfunction was not required for enrollment in this trial, it is unknown which patients truly had the condition. Accordingly, the exact role of digoxin in the treatment of diastolic heart failure remains unclear.

Maintenance of synchrony of atrial and ventricular contractions is required for preservation of normal filling patterns. Whenever possible, atrial fibrillation should be converted to sinus rhythm. If maintenance of sinus rhythm is not possible, the ventricular rate should be well controlled through use of drugs or ablation of the atrioventricular node, if necessary.

Prognosis

Diastolic dysfunction often is discovered in a previously symptom-free patient during a laboratory test performed for other indications, such as hypertension, valve disease, or CAD. The survival of patients without heart failure or other symptoms of diastolic dysfunction has not been thoroughly examined in well-done community-based studies (16). It is reasonable to assume that coexistent conditions that cause diastolic dysfunction, such as hypertension or CAD, are more powerful determinants of a person's longevity than the presence of diastolic dysfunction itself. It is also reasonable to postulate that diastolic dysfunction is a potent risk factor for clinical heart failure, although the exact incidence of this event in previously asymptomatic persons with diastolic dysfunction also is unknown.

Short-term survival among patients with a normal ejection fraction who are hospitalized for heart failure is better than survival among those with a low ejection fraction but worse than that of age-matched control subjects without heart failure. Diastolic heart failure is a major cause of cardiovascular morbidity, especially in the elderly population (4,5,16). Clinical disability, lifestyle impairment, and rehospitalization rates are similar among heart failure patients with low versus normal ejection fraction.

Conclusion

Diastolic dysfunction is a common condition that is highly prevalent among elderly persons. A host of cardiac disorders predispose to diastolic dysfunction, including hypertension, ischemic heart disease, myocardial hypertrophy, and infiltrative cardiomyopathies. Exercise, tachycardia, anemia, fever, and many systemic illnesses may provoke symptomatic decline in patients with this condition.

Diagnosis of diastolic dysfunction relies on careful clinical bedside evaluation supplemented with a laboratory workup. Of diagnostic procedures, two-dimensional and Doppler echocardiographic techniques are uniquely suited to evaluate the changes in left ventricular structure and physiology that are typical in diastolic dysfunction.

Successful treatment of diastolic dysfunction includes preventive measures focused on hypertension, left ventricular hypertrophy, and atherosclerotic heart disease. When acute exacerbations occur, intravascular volume reduction, heart rate control, and elimination of precipitating factors are essential. Diuretics, beta-blockers, and ACE inhibitors are particularly useful in prevention and treatment. Patients with diastolic dysfunction can anticipate improved functional capacity and perhaps improved long-term outcomes with careful clinical management.

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The effect of digoxin on mortality and morbidity in patients with heart failure. Digitalis Investigation Group. N Engl J Med 1997;336(8):525-33

Senni M, Redfield MM. Heart failure with preserved systolic function: a different natural history? J Am Coll Cardiol 2001;38(5):1277-82

Dr Torosoff is assistant professor of medicine and Dr Philbin is George E. Pataki Chair in Cardiology, division of cardiology, department of medicine, Albany Medical College, Albany, New York. Correspondence: Edward F. Philbin, MD, George E. Pataki Chair in Cardiology, Albany Medical College, Mail Code 44, 47 New Scotland Ave, Albany, NY 12208. E-mail: philbie@mail.amc.edu.

[Ace844]

Hi All,

Here's a link with soem good clinical info./RX of CHF from here::: Chest pain and breathing difficulty

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Ace844

[Nate]

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[Ace844]

TABLE 4 Clues for Differentiating Between Systolic and Diastolic Dysfunction in Patients with Heart Failure

Clues from the evaluation Systolic dysfunction Diastolic dysfunction

History

Hypertension XX XXX

Coronary artery disease* XXX X

Diabetes mellitus XXX XX

Valvular heart disease* XXX --

Physical examination

Third heard sound (S3) gallop* XXX X

Fourth heart sound (S4) gallop* X XXX

Rales XX XX

Jugular venous distention XX X

Edema XX X

Displaced point of maximal impulse* XX --

Mitral regurgitation* XXX X

Chest radiograph

Cardiomegaly* XXX X

Pulmonary congestion XXX XXX

Electrocardiogram

Q wave XX X

Left ventricular hypertrophy* X XXX

Echocardiogram

Decreased ejection fraction* XXX --

Dilated left ventricle* XX --

Left ventricle hypertrophy* X XXX

X = suggestive; the number of Xs reflects the relative weight; -- = not suggestive.*--Particularly helpful in distinguishing systolic from diastolic dysfunction in heart failure.Adapted with permission from Young JB. Assessment of heart failure. In: Braunwald E. Atlas of heart disease. Vol 4. Philadelphia: Current Medicine, 1995:7.1-7.2.

Treatment of Diastolic or Systolic Dysfunction

*--Diuretics are best used to treat acute congestive heart failure and as adjunctive therapy for hypertension.†--Note that the likelihood of angioedema and renal insufficiency is increased with ACE inhibitors and angiotensin-receptor blockers. Watch for late-breaking results from clinical trials on the efficacy of angiotensin-receptor blockers alone and in combination with ACE inhibitors compared with ACE inhibitors alone.‡--The addition of milrinone is preferred in patients already receiving a beta blocker.

Table 1--Cardiac Pump Function During and After Acute Hypertensive

Pulmonary Edema *

DHF Compared to SHF

SHF (n = 20) DHF (n = 18) (n = 18) %

Variables During After During After During After

LVEDV, mL 131 138 85 94

LVESV, mL 78 83 36 37

LVSV, mL 53 55 49 57 -7 +3

HR, beats/min 87 77 79 66 -9 -15

LVEF, % 40 40 58 61 +43 +52

CO, L/min 4.6 4.3 3.9 3.8 -15 -12

* Derived from Gandhi et al. (1) Since their article included no HR or

volume data for the SHF group, these data were computed via spreadshhet

from the published DHF and combined DHF-SHF values. To achieve the best

approximation of the original observations (available from the author),

LVEF values were then calculated from the computed volumes, minor

deviations anticipated due to precision/rounding error. LVES = LV

end-systolic volume; LVSV = LV stroke volume; LVEDV = left ventricular

end-diastolic volume.

Table 2--LVEF: Meaningless in Terms of Cardiac

Output Without the Coexisting LVEDV *

Variables Normal SHF DHF-1 DHF-2 SDf

LVEDV, mL 120 250 100 85 200

LVESV, mL 50 200 50 35 130

LVSV, mL 70 50 50 50 70

HR, beats/min 60 60 60 60 60

LVEF, % 60 20 50 60 35

CO, L/min 4.2 3.0 3.0 3.0 4.2

[DELTA]CO, from normal, % 0 -30 -30 -30 0

* Derived from Braunwald et al, (9) whose angiographic volume indexes

are converted here to absolute volumes using nominal body surface

area (1.73 [m.sup.2] and liberal rounding to facilitate interpretation

(but in all cases <2%). DHF-1 = DHF due to mild-to-moderate DDf;

DHF-2 = DHF due to severe DDf; SDf = systolic dysfunctions

without HF; see Table 1 for expansion of abbreviates.

*****>>>>NOTE:::: I was unable to post all of them as my "flow charts" wouldn't copy onto the board and i couln't figure out how to post them.....So is anyone knows how and is willing to share that I will Post the others... Also, you can PM me with your e-mail and I'll send it in MS word to you....>>>>>*******

Hope this helps,

Ace844

[Ace844]

Part 3

SYSTOLIC DYSFUNCTION

Systolic vs. Diastolic Dysfunction

As many as 40 percent of patients with clinical heart failure have diastolic dysfunction with normal systolic function.32 In addition, many patients with systolic dysfunction have elements of diastolic dysfunction. With systolic dysfunction, the pumping ability of the ventricle is impaired. With diastolic dysfunction, ventricular filling is defective.Ventricular diastolic function depends on the pressure-to-volume relationship in the left ventricle. Decreased compliance of the left ventricular wall leads to a higher pressure for a given diastolic volume. The end result is impaired ventricular filling, inappropriately elevated left atrial and pulmonary venous pressure, and decreased ability to increase stoke volume. These dysfunctions lead to the clinical syndrome of heart failure. Findings suggestive of diastolic dysfunction on the two-dimensional echocardiogram are left ventricular hypertrophy, a dilated left atrium, a normal or nearly normal ejection fraction and reversal of the normal pattern of flow velocity (measured by Doppler flow studies) across the mitral valve (Figures 3 and 4).

Systolic Dysfunction Disorders that cause systolic dysfunction may impair the entire heart or one area of the heart. As a result, the heart does not contract normally. Coronary artery disease is a common cause of systolic dysfunction. It can impair large areas of heart muscle because it reduces the flow of oxygen-rich blood to the heart muscle, which needs oxygen for normal contraction. Blockage of a coronary artery can cause a heart attack, which destroys an area of heart muscle. As a result, that area can no longer contract normally.

Myocarditis (inflammation of heart muscle) caused by a bacterial, viral, or other infection can damage all or part of the heart muscle, impairing its pumping ability.

Heart valve disorders—narrowing (stenosis) of a valve, which hinders blood flow through the heart, or leakage of blood backward (regurgitation) through a valve—can cause heart failure. Both stenosis and regurgitation of a valve can severely stress the heart, so that over time, the heart enlarges and cannot pump adequately. An abnormal connection (septal defects (see Birth Defects: Atrial and Ventricular Septal Defects and Septal Defect: A Hole in the Heart's Wall ) between the heart chambers can allow blood to recirculate within the heart, increasing the workload of the heart, and thus can cause heart failure.

Disorders that affect the heart's electrical conduction system, producing changes in heart rhythms, (especially if heartbeats are fast or irregular), can cause heart failure. When the heart beats abnormally, it cannot pump blood adequately.

Some lung disorders, such as pulmonary hypertension (see Pulmonary Hypertension), may alter or damage blood vessels in the lungs. As a result, the heart has to work harder to pump blood into the arteries that supply the lungs (pulmonary arteries). Pulmonary hypertension may lead to cor pulmonale (see Cor Pulmonale: A Disorder Stemming From Pulmonary Hypertension ). In this disorder, the right ventricle, which pumps blood to the lungs, becomes enlarged, eventually resulting in right-sided heart failure. Sudden, usually complete blockage of a pulmonary artery by several small blood clots or one very large clot (pulmonary embolism) also makes pumping blood into the pulmonary arteries difficult. A very large clot can be immediately life threatening. The increased effort required to pump blood into the blocked pulmonary arteries can cause the right side of the heart to enlarge and may cause the walls of the right ventricle to thicken, resulting in right-sided heart failure.

Disorders that indirectly affect the heart's pumping ability include a deficiency of red blood cells or hemoglobin (anemia), an overactive thyroid gland (hyperthyroidism), an underactive thyroid gland (hypothyroidism), and kidney failure. Red blood cells contain hemoglobin, which enables them to carry oxygen from the lungs and deliver it to body tissues. Anemia reduces the amount of oxygen the blood carries, so that the heart must work harder to provide the same amount of oxygen to tissues. (Anemia has many causes, including chronic bleeding due to a stomach ulcer). An overactive thyroid gland overstimulates the heart, so that it pumps too rapidly and does not empty normally during each heartbeat. When the thyroid gland is underactive, levels of thyroid hormones are low. As a result, all muscles, including the heart, become weak because muscles depend on thyroid hormones to function normally. Kidney failure strains the heart because the kidneys cannot remove excess fluid from the bloodstream, so the heart has to pump more blood. Eventually, the heart cannot keep up, and heart failure develops.

Causes of systolic heart failure

Systolic heart failure can result from numerous and diverse causes (table 2). Identifying the cause is important, since appropriate treatment may reverse the process (eg, revascularization for ischemic heart disease and therapy for certain systemic disorders, such as thyroid replacement for hypothyroidism). If the underlying disorder is not treated promptly, left ventricular dysfunction is likely to be permanent.

Table 2. Causes of systolic heart failure

Coronary artery diseaseHypertensionMetabolic disorderThyroid diseaseVitamin deficiencyDiabetes mellitusInfectionToxin exposureCobaltChemotherapeutic agentsAlcoholCocaineInfiltrative diseaseCardiac amyloidosisHemochromatosisOtherNeuromuscular diseaseCollagen vascular diseaseValvular heart diseasePeripartum cardiomyopathyHigh-output heart failure Arteriovenous fistula Severe anemia Paget's diseaseIdiopathicChronic viral myocardial infection?Autoimmune mechanisms?Genetic factors?

Coronary artery disease

Ischemic coronary artery disease, with or without myocardial infarction, is the most common cause of CHF. Systolic heart failure may be a transient condition occurring around the time of acute infarction or an ongoing problem resulting from loss of myocardial tissue (3). Patients with ischemic heart disease may show improved ventricular function after revascularization, especially those with myocardial hibernation (left ventricular segments that are still viable, even though the segments may be chronically underperfused and hypocontractile). Revascularization of these segments may decrease the likelihood of CHF and improve survival (4,5).

Hypertension

Long-standing hypertension, particularly when it is poorly controlled, may lead to CHF. Both systolic and diastolic blood pressure play an important role (6). The incidence of CHF is higher in patients with electrocardiographic (ECG) criteria indicative of left ventricular hypertrophy, especially when repolarization abnormalities are present. ST- and T-wave changes may indicate subendocardial ischemia, which contributes further to cardiac dysfunction (1).

Metabolic disorders

Thyroid abnormalities can be responsible for CHF, especially in elderly patients. Thyroid hormone is a direct cardiac stimulant and can increase contractility and systolic performance. In hypothyroidism, lack of circulating thyroxine (T4) causes down-regulation of myocardial beta-adrenergic receptors and may modify the contractile process, leading to CHF. Patients with a structurally normal heart usually can tolerate excess thyroid hormone without experiencing compromised cardiac function. However, when underlying heart disease is present, hyperthyroidism may precipitate systolic heart failure; angina is often an early symptom. Arrhythmias, particularly atrial fibrilation and other supraventricular tachycardias, may worsen already-compromised cardiac function. Symptoms and signs of systolic dysfunction usually improve with treatment of thyroid disease.

Other metabolic disorders that may lead to development of CHF include vitamin deficiencies (eg, thiamine, ascorbic acid), endocrine abnormalities (eg, acromegaly, diabetes mellitus, pheochromocytoma), and rare disorders (eg, porphyria).

Infectious diseases

Infection can be an important cause of dilated cardiomyopathy and may present as acute myocarditis, which may or may not improve with treatment. CHF symptoms usually do not present until several weeks after the initial infection, suggesting a possible immunologic mechanism for development of systolic dysfunction.

The most common viral cause of myocarditis is coxsackievirus B, but at least two dozen others, including hepatitis viruses, adenovirus, arbovirus, cytomegalovirus, echovirus, influenza virus, and HIV, are also possibilities.

Bacterial myocarditis (distinct from rheumatic carditis) is very uncommon. Rarely, it complicates the clinical course in patients with fulminant disease secondary to infection with brucella, clostridium, salmonella, toxigenic strains of Corynebacterium diphtheriae, Legionella pneumophila, meningococcus, and streptococcus. Lyme disease can cause myocarditis that may lead to transient left ventricular dysfunction or heart block.

In Central and South America, infection with the protozoa Trypanosoma cruzi (the causative agent in Chagas' disease) may result in acute myocarditis with development of biventricular heart failure many years later.

Toxin exposure

Exposure to several toxic substances, including cobalt and such chemotherapeutic agents as doxorubicin hydrochloride (Adriamycin, Rubex), may cause dilated cardiomyopathy. Long-term alcohol use is a leading cause of CHF, and cocaine abuse may also contribute to development of systolic dysfunction.

Infiltrative disease

Some diseases, such as cardiac amyloidosis and hemochromatosis, can progress to severe systolic dysfunction.

Other causes

Neuromuscular disease, collagen vascular disease, valvular heart disease, peripartum cardiomyopathy, and high-output heart failure (eg, from arteriovenous fistulas, severe anemia, Paget's disease) also may result in CHF.

Finally, in many patients, dilated cardiomyopathy has no clear cause. Possible explanations have included chronic viral myocardial infection, autoimmune mechanisms, and genetic factors that directly contribute to development of the disease (7).

Heart Failure Society Of America: Guidelines for Management of Patients with Heart Failure Caused by Left Ventricular Systolic Dysfunction-Pharmacological Approaches

Treatment of Diastolic or Systolic Dysfunction

*--Diuretics are best used to treat acute congestive heart failure and as adjunctive therapy for hypertension.†--Note that the likelihood of angioedema and renal insufficiency is increased with ACE inhibitors and angiotensin-receptor blockers. Watch for late-breaking results from clinical trials on the efficacy of angiotensin-receptor blockers alone and in combination with ACE inhibitors compared with ACE inhibitors alone.‡--The addition of milrinone is preferred in patients already receiving a beta blocker.

FIGURE 5. Suggested algorithm for the treatment of diastolic or systolic dysfunction. (ACE = angiotensin-converting enzyme; NYHA = New York Heart Association; IV = intravenous.)

Differentiating between systolic and diastolic dysfunction is essential because their long-term treatments are different33 (Table 434 and Figure 5). The treatments of choice in patients with systolic dysfunction are ACE inhibitors, digoxin, diuretics and beta blockers. In patients with diastolic dysfunction, the cornerstones of treatment depend on the underlying cause. Beta blockers and calcium channel blockers are frequently used when diastolic dysfunction is secondary to ischemia or hypertension.

The history, physical examination, ECG and chest radiographs provide some clues that can be helpful in differentiating systolic and diastolic dysfunction. For example, predominantly systolic dysfunction is suggested by a history of myocardial infarction and younger patient age, a displaced point of maximal impulse and an S3 gallop on the physical examination, the presence of Q waves on the ECG and the finding of cardiomegaly on the chest radiograph. In contrast, diastolic dysfunction is suggested by a history of hypertension and older patient age, a sustained point of maximal impulse and an S4 gallop on the physical examination, left ventricular hypertrophy on the ECG and a normal-sized heart on the chest radiograph.36 However, the findings can overlap considerably, and echocardiography of the heart is usually necessary.

I. Treatment of Acute CHF Secondary to Systolic Dysfunction

A. Precipitators of acute pulmonary edema (in a previously compensated patient). Poor compliance with medical or diet therapy, increased metabolic demands (infection, especially pneumonia, pregnancy, anemia, hyperthyroidism), progression of underlying heart disease, arrhythmias (e.g., tachycardia), drug effect (beta-blockers, calcium-channel blockers, other negative inotropes), silent MI, pulmonary embolism.

B. Diagnosis.

The diagnosis of pulmonary edema is usually made initially by physical exam and confirmed by CXR. Treatment may have to be started before one obtains a detailed history, etc. However, once the patient is stable, a careful work-up should be undertaken to determine underlying causes and precipitating factors.

1. History. Past history of cardiac and pulmonary disease or hypertension. History of shortness of breath, orthopnea, dyspnea on exertion, faintness, chest pain. Recent weight gain, edema. Recent infection, exposure to toxic inhalants, smoke, possible aspiration. Current medication regimen, compliance with diet and medications. However, PND and orthopnea are not specific for CHF.

2. Physical exam. Tachypnea, tachycardia, often BP is elevated. If patient has fever, suspect concurrent infection, which may increase metabolic demand and lead to CHF. Cyanosis, diaphoresis, retractions, use of accessory muscles of respiration, wheezing ("cardiac asthma"), and rales on lung auscultation. Cough may be productive of pink, frothy sputum. Listen for S3 gallop or murmurs. Peripheral edema and positive hepatojugular reflux are suggestive of CHF, and bruits may be a clue to underlying vascular disease.

C. Diagnostic tests.

1. Lab tests. Electrolytes, BUN, creatinine, cardiac enzymes, serum protein and albumin, urinalysis, differential CBC count, and ABG.

2. CXR. Initially will show interstitial edema as well as thickening and loss of definition of the shadows of pulmonary vasculature. Fluid in septal planes and interlobular fissures cause the characteristic appearance of Kerley A and B lines. Eventually, pleural effusions and perihilar alveolar edema may develop in the classic "butterfly" pattern. CXR findings may lag behind the clinical presentation by up to 12 hours and may take 4 days to clear after clinical improvement in the patient.

3. EKG. Evaluate for evidence of MI and arrhythmia. The sudden onset of atrial fibrillation or PSVT may cause acute decompensation in previously stable chronic CHF. LVH may signal underlying aortic stenosis, hypertension, or cardiomyopathy.

4. Echocardiography. Not imperative acutely. In work-up for underlying cause, it is useful to evaluate for valvular disease, valvular vegetations, wall-motion abnormalities, LV function, and cardiomyopathy.

D. Treatment

1. Oxygen. By nasal cannula or mask. May require endotracheal intubation if unable to adequately oxygenate despite use of 100% oxygen by non-rebreather mask. Mask continuous positive airway pressure (CPAP) has been shown to reduce the need for intubation and is an excellent alternative.

2. Other general measures. Elevate head of bed 30 degrees. May need Swan-Ganz catheter for hemodynamic monitoring if the patient becomes hypotensive. However, Swan-Ganz catheters may have an adverse effect on mortality and should be used only after careful consideration. If indicated, place a Foley catheter for fluid management.

3. Medications.

a. Vasodilators are considered the first drug of choice in acute CHF and act by preload and afterload thereby decreasing LV work. May also reverse myocardial ischemia. IV nitroglycerin is commonly used, especially if there is concern that ischemia is an underlying or precipitating factor. Start at 10 to 20 mg/min and increase by increments of 10 to 20 mg/min Q5 min until the desired effect is achieved. Sublingual nitroglycerin 0.4 mg repeated Q5 min PRN can also be used acutely as can topical nitrates. However, topical nitrates may not be effective acutely with a maximal effect at 120 minutes. Nitroprusside is an alternative (start at 0.5 mg/kg/ min and increase by 0.5 mg/kg/min Q5 min). Most patients respond to less than 10 mg/kg/min but titrate to effect. Nitroprusside is more likely to cause hypotension than is IV nitroglycerin. A fluid bolus may help to reverse nitrate-induced hypotension but should be used judiciously in those with CHF.

b. Furosemide and other diuretics. If the patient has never been treated with furosemide may start with 20 mg IV and observe response. Titrate dose upward until adequate diuresis is established. If the patient is receiving furosemide over a long-term give 1 to 2 times the usual daily dose by slow (over 1 to 2 minutes) IV bolus. Larger doses (up to 1 g) may be needed in those patients receiving large doses or with a history of renal disease. Alternatively, a furosemide drip can be established for higher doses. Give 20% of the dose as a bolus (that is, 200 mg) and infuse the rest over 8 hours. This has a greater efficacy than a single, large bolus does. Up to 2 g has been safely administered in this fashion. Ethacrynic acid 25 to 100 mg IV may be needed if the patient does not respond to furosemide. Bumetanide (0.5 to 1.0 mg IV) may also be used. Adding metolazone (5 to 20 mg) or chlorothiazide 500 mg IV to furosemide may generate additional diuresis. Some authors would consider phlebotomy if diuretics are ineffective and patient has a high HCT, but this is a high risk procedure.

c. Morphine acts as a venodilator and decreases anxiety. Start with 1 to 2 mg IV. Tritiate carefully in COPD and CHF, since narcotics can decrease respiratory drive.

d. ACE inhibitors can be used acutely in the management of CHF but are more common as chronic therapy. Captopril 12.5 to 25 mg SL or IV at 0.16 mg/min increased by 0.08 mg/min every 5 minutes until it has the desired effect. This is safe and effective and should can be used in patients unresponsive to oxygen, nitrates and diuretics.

e. Dobutamine (2.5 to 15 mg/kg/min) or dopamine (2 to 20 mg/kg/ min) may be needed for pressure support or as a positive inotrope. These drugs are effective immediately; however, al- though dopamine increases renal perfusion, it may not increase GFR.

f. Digoxin. Check ECG, serum potassium, BUN, and creatinine first before loading with digoxin. After digoxin loading, it may be difficult to distinguish ischemic changes on ECG from digoxin effect. Inquire about previous use of digoxin and any adverse reactions. Determine if patient has any history of renal, pulmonary, liver, or thyroid disease. Be aware of other medications that the patient takes that might affect digoxin levels such as amiodarone, flecainide, quinidine, and verapamil. Decrease digoxin dose if the patient has renal disease. The aim is to achieve serum levels of 1.0 to 1.5 ng/ml.

4. Surgery may be indicated under rare conditions such as valvular heart disease or rupture of ventricular septum after an MI. In severe LV failure, an intra-aortic balloon pump may be beneficial as a temporizing measure.

II. Outpatient Treatment of CHF Secondary to Systolic Dysfunction

A. Nonpharmacologic therapy.

Avoid excessive physical stress, reduce dietary salt, consider compressive stockings if needed to reduce risk of DVT (consider SQ heparin if inpatient), and weight loss if obese. Work on walking and endurance training.

B. Pharmacologic therapy.

1. Drugs that have been shown to reduce mortality in CHF: ACE inhibitors, beta-blockers (e.g., metoprolol), spironolactone and the combination of hydralazine + isosorbide dinitrate.

2. Diuretics. Loop diuretics are usually recommended (e.g., furosemide). Some patients develop resistance to loop diuretics after chronic usage. A single dose of metolazone (5 to 20 mg QD) will often result in significant diuresis in such patients. Patients with heart failure who are receiving diuretics should have potassium and magnesium levels monitored. Supplementation should be provided if necessary, since hypokalemia and hypomagnesemia are risk factors for the development of arrhythmias. The use of spironolactone at low dose (25 mg QD) has recently been shown to reduce morbidity in patients even if already treated with a standard therapy, including loop diuretics (RALES trial).

3. ACE inhibitors. These agents function primarily as afterload reducers and have been shown to reduce morbidity (CHF progression, MI, need for hospitalization) and mortality. ACE inhibitors also improve hemodynamics and increase exercise tolerance in heart failure. Up to now only captopril, enalapril, lisinopril, and ramipril have been shown to be efficacious in large controlled clinical trials however, it is likely a class specific effect. Begin therapy at low doses such as enalapril 2.5 mg PO BID and titrate to 10 mg PO BID gradually. Observe the patient for hypotension or persistent cough. Monitor electrolytes and renal function because ACE inhibitors can cause elevation of serum potassium and can cause a reversible decrease in renal function in some patients. Patients at high risk for adverse effects from ACE inhibitors include those with connective tissue diseases, preexisting renal insufficiency, or bilateral renal artery stenosis. Contraindications to their use include a history of hypersensitivity to ACE inhibitors, serum potassium greater than 5.5 mEq/L (consider evaluation for hypoaldosteronism or Addison’s disease), or a previous episode of angioedema during their use. Relative contraindications include renal failure and hypotension. However, ACE inhibitors actually protect renal function in those with chronic renal failure (see Chapter 8 for details). In the latter two patient groups, ACE inhibitor therapy should be initiated at half the usual starting dose and titrated to desired effect.

4. Beta-blockers. The use of beta-blockers in patients with CHF caused by systolic dysfunction is now the standard of care. The initiation and titration of these medications should be undertaken with care. The studied agents that are recommended are carvedilol and metoprolol (specifically Toprol-XL). These agents appear to confer myocardial protection by inhibiting a variety of damaging neurohumoral effects activated by CHF.

5. Angiotensin-receptor blockers (ARBs) function by afterload reduction and have been shown to have an equivalent effect to ACE inhibitors. The limitations of ACE inhibitors (cough, angioedema) are not prevalent with these agents; however, their effects on renal function are still under investigation. They should not supplant ACE inhibitors but can be substituted for them for patients who are intolerant of ACE-I. The results of studies investigating the combined use of ARBs with ACE inhibitors are not yet known.

6. Other vasodilators. ACE-I therapy increases survival in heart failure more than the combination hydralazine and isosorbide therapy. However, in patients unable to tolerate ACE inhibitors or an ARB, a combination of hydralazine and isosorbide dinitrate may be used.

7. Digoxin is shown to improve symptoms in severe heart failure and in cases where atrial fibrillation is a complication of CHF. However, digoxin has no effect on mortality because of a proarrhythmic effect and should be considered a measure for symptom control only. Rapid digitalization is not necessary in patients with chronic CHF. The half-life of digoxin is 11/2 to 2 days in patients with normal renal function. The usual starting dose is 0.25 mg/day. Decrease the dose in small or elderly patients and in those receiving other drugs (such as quinidine, amiodarone, and verapamil) that raise digoxin levels. Decrease the dose in patients with impaired renal function. Monitor levels, especially after dose adjustments or after changes in other medications that may affect digoxin levels (such as quinidine, verapamil, and oral azole antifungals). Avoid digoxin in patients with idiopathic hypertrophic subaortic stenosis (IHSS) and those with diastolic dysfunction. Watch potassium levels closely; hypokalemia renders the heart more sensitive to digoxin and will predispose to digoxin toxicity.

8. Intermittent intravenous inotrope infusions. Dobutamine is the parenteral inotropic agent of choice in severe, chronic CHF. Onset of action is immediate and stops quickly when the infusion is discontinued. It should not be used in patients with IHSS except in consultation with a cardiologist. May cause tachycardia, angina, and ventricular arrhythmias. Alternatively, Milrinone may be used to both improve contractile functions and cause some degree of vasodilation. May cause ventricular arrhythmias. Effect of these modalities on mortality is not yet known.

9. Calcium-channel blockers. Some calcium-channel blockers, especially verapamil and diltiazem, are relatively potent negative inotropic agents and should generally be avoided in patients with poor LV function. In patients with CHF and hypertension, amlodipine (a second-generation dihydropyridine calcium-channel blocker with no negative inotropic effect) has been shown to be efficacious.

10. Antithrombotic therapy. Patients with a previous history of embolism or A fib are at high risk for thromboembolic complications and should be considered for warfarin therapy unless a contraindication exists. Titrate the dose to an INR of 2.0 to 3.0 (prothrombin time not more than 1.5 times normal) to avoid increased risk of bleeding complications. If warfarin cannot be used, consider aspirin for the antiplatelet effect (80 to 300 mg/day).

11. Ventricular Assist Devices (VADs). These devices have been shown to improve morbidity and survival in selected patients waiting to undergo transplantation. The decision to implant such a device should be made only after careful evaluation by a surgeon trained in their insertion. Follow-up care involves close collaboration with transplant facility. VADs are being studied as stand-alone therapy for patients not considered candidates for transplantation.

III. Follow-up.

Once the acute episode of pulmonary edema is under control, a careful search for the underlying cause must be undertaken. Further work-up might include echocardiography to evaluate valve function and chamber size, radionuclide studies to evaluate LV and RV ejection fraction and wall motion, and cardiac catheterization.

IV (IHSS) most commonly presents in young adults before the third decade.

A. Etiology and Examination.

Caused by a thickened septum impinging on anterior mitral leaflet and creating a dynamic obstruction in the left ventricular outflow tract. It is an autosomal dominant mutation, 50% penetrance, male/female equal occurrence. Signs are commonly dyspnea, angina, syncope, and fatigue. Examination is notable for a laterally displaced apical impulse, rapid rise and biphasic carotid pulse, variably split S2 and loud S4, harsh crescendo-decrescendo murmur at the lower left sternal border and apex. The murmur classically increases and lengthens with Valsalva, decreases with handgrip.

B. Management and Treatment

Aimed at reducing ventricular rate, allowing increased ventricular volume and outflow tract dimensions. Most commonly beta-blockers or calcium channel blockers. Do not use digitalis preparations. Avoiding strenuous physical activity, especially competitive sports. Some recommend AV sequential pacing. Surgical therapy may be helpful in selected cases, with left ventricular myomectomy or heart transplantation for cases with severe left ventricular failure.

TABLE 4Clues for Differentiating Between Systolic and Diastolic Dysfunction in Patients with Heart Failure

Clues from the evaluation Systolic dysfunction Diastolic dysfunction

History

Hypertension XX XXX

Coronary artery disease* XXX X

Diabetes mellitus XXX XX

Valvular heart disease* XXX --

Physical examination

Third heard sound (S3) gallop* XXX X

Fourth heart sound (S4) gallop* X XXX

Rales XX XX

Jugular venous distention XX X

Edema XX X

Displaced point of maximal impulse* XX --

Mitral regurgitation* XXX X

Chest radiograph

Cardiomegaly* XXX X

Pulmonary congestion XXX XXX

Electrocardiogram

Q wave XX X

Left ventricular hypertrophy* X XXX

Echocardiogram

Decreased ejection fraction* XXX --

Dilated left ventricle* XX --

Left ventricle hypertrophy* X XXX

X = suggestive; the number of Xs reflects the relative weight; -- = not suggestive.*--Particularly helpful in distinguishing systolic from diastolic dysfunction in heart failure.Adapted with permission from Young JB. Assessment of heart failure. In: Braunwald E. Atlas of heart disease. Vol 4. Philadelphia: Current Medicine, 1995:7.1-7.2.

Assessment of Left-Ventricular Function

Physical Examination

Coronary artery disease and hypertension are the leading causes of heart failure.

A complete physical examination is the second component in the diagnosis of heart failure. The patient's general appearance should be assessed for evidence of resting dyspnea, cyanosis and cachexia.

Blood Pressure and Heart Rate

The patient's blood pressure and heart rate should be recorded. High, normal or low blood pressure may be present. The prognosis is worse for patients who present with a systolic blood pressure of less than 90 to 100 mm Hg when not receiving medication (angiotensin-converting enzyme [ACE] inhibitors, beta blockers or duretics).16 Tachycardia may be a sign of heart failure, especially in the decompensated state. The heart rate increases as one of the compensatory ways of maintaining adequate cardiac output. A decrease in the resting heart rate with medical therapy can be used as a surrogate marker for treatment efficacy. A weak, thready pulse and pulsus alternans are associated with decreased left ventricular function. The patient should also be monitored for evidence of periodic breathing (Cheyne-Stokes respiration).

TABLE 3New York Heart Association Functional Classification of Congestive Heart Failure

The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication.

Jugular Venous Distention

Jugular venous distention is assessed while the patient is supine with the upper body at a 45-degree angle from the horizontal plane. The top of the waveform of the internal jugular venous pulsation determines the height of the venous distention. An imaginary horizontal line (parallel to the floor) is then drawn from this level to above the sternal angle. A height of more than 4 to 5 cm from the sternal angle to this imaginary line is consistent with elevated venous pressure (Figure 1).

FIGURE 1. Assessment of jugular venous distention.

Elevated jugular venous pressure is a specific (90 percent) but not sensitive (30 percent) sign of elevated left ventricular filling. The reproducibility of the jugular venous distention assessment is low.17

Point of Maximal Impulse

The point of maximal impulse of the left ventricle is usually located in the midclavicular line at the fifth intercostal space. With the patient in a sitting position, the physician uses fingertips to identify this point. Cardiomegaly usually displaces the cardiac impulse laterally and downward. At times, the point of maximal impulse may be difficult to locate and therefore loses sensitivity (66 percent). Yet the location of this point remains a specific indicator (96 percent) for evaluating the size of the heart.14

Third and Fourth Heart Sounds

A double apical impulse can represent an auscultated third heart sound (S3). Just as with the displaced point of maximal impulse, a third heart sound is not sensitive (24 percent) for heart failure, but it is highly specific (99 percent).14 Patients with heart failure and left ventricular hypertrophy can also have a fourth heart sound (S4). The physician should be alert for murmurs, which can provide information about the cause of heart disease and also aid in the selection of therapy.

Pulmonary Examination

Physical examination of the lungs may reveal rales and pleural effusions. Despite the presence of pulmonary congestion, rales can be absent because of increased lymphatic drainage and compensatory changes in the perivascular structures that have occurred over time. Wheezing may be the sole manifestation of pulmonary congestion. Frequently, asthma is erroneously diagnosed in patients who actually have heart failure.

Liver Size and Hepatojugular Reflux

The key component of the abdominal examination is the evaluation of liver size. Hepatomegaly may occur because of right-sided heart failure and venous congestion. The hepatojugular reflux can be a useful test in patients with right-sided heart failure. This test should be performed while the patient is lying down with the upper body at a 45-degree angle from the horizontal plane. The patient keeps the mouth open and breathes normally to prevent Valsalva's maneuver, which can give a false-positive test. Moderate pressure is then applied over the middle of the abdomen for 30 to 60 seconds. Hepatojugular reflux occurs if the height of the neck veins increases by at least 3 cm and the increase is maintained throughout the compression period.18

Lower Extremity Edema

Lower extremity edema, a common sign of heart failure, is usually detected when the extracellular volume exceeds 5 L. The edema may be accompanied by stasis dermatitis, an often chronic, usually eczematous condition characterized by edema, hyperpigmentation and, commonly, ulceration.

Valsalva's Maneuver

Valsalva's maneuver is rarely used in the evaluation of patients with heart failure. Yet this test is simple to perform and carries one of the best combinations of specificity (91 percent) and sensitivity (69 percent) for the detection of left ventricular systolic and diastolic dysfunction in patients with heart failure.19,20

Valsalva's maneuver is performed with the blood pressure cuff inflated 15 mm Hg over the systolic blood pressure. While the physician auscultates over the brachial artery, the patient is asked to perform a forced expiratory effort against a closed airway (the Valsalva's maneuver). A normal response would be an initial rise in systolic blood pressure at the onset of straining (phase I) with Korotkoff's sounds heard (Figure 2). While the maneuver is maintained (phase II), a decrease in the blood pressure occurs with loss of Korotkoff's sounds. Release of the maneuver (phase III) is followed by an overshoot of blood pressure and the reappearance of heart sounds (phase IV). Abnormal responses occurring in patients with heart failure are maintenance of beats throughout Valsalva's maneuver (square wave) or lack of reappearance of Korotkoff's sounds after release of the maneuver (absent overshoot).

FIGURE 2. Arterial blood pressure response and Korotkoff's sounds during Valsalva's maneuver. (A) Sinusoidal response in normal patient. ( Absent overshoot in patient with heart failure. © Square wave response in patient with heart failure. The red lines indicate when Korotkoff's sounds are heard. (BP = blood pressure)

Diagnostic Challenges

Diagnosing heart failure in elderly patients may be particularly challenging because of the atypical presentations in this age group. Anorexia, generalized weakness and fatigue are often the predominant symptoms of heart failure in geriatric patients. Mental disturbances and anxiety are also common.

When older persons become symptomatic on exertion, they decrease their level of activity to the point of becoming relatively asymptomatic. A cycle of symptoms on exertion and consequent decrease in activity frequently continues as the disease progresses, until the patient finally becomes symptomatic at rest (i.e., NYHA class IV).

The physical findings in older patients with heart failure may be difficult to interpret accurately. Resting tachycardia is uncommon, and pulse contour abnormalities are difficult to assess secondary to peripheral arteriosclerotic changes. At times, auscultatory findings on the lung examination are atypical because of concomitant pulmonary disease.21

Patients with suspected heart failure should undergo echocardiography or radionuclide ventriculography to measure EF (if information about ventricular function is not available from previous tests). (Strength of Evidence = B.)

Measurement of left-ventricular performance is a critical step in the evaluation and management of almost all patients with suspected or clinically evident heart failure. The combined use of history, physical examination, chest x-ray, and electrocardiography cannot be relied on to distinguish between the major etiologies of heart failure: left-ventricular systolic dysfunction (i.e., EF < 35-40 percent), left-ventricular diastolic dysfunction (i.e., heart failure occurring despite EF 40 percent), valvular heart failure disease, or a noncardiac etiology. A substantial proportion (up to 40 percent in some studies) of patients with signs and symptoms of heart failure have EF's greater than 50 percent. [26, 29, 30, 68, 69] These patients generally have valvular disease, intermittent ischemia, or ventricular diastolic dysfunction. If measurement of ventricular performance is not obtained in these patients, inappropriate treatments may be instituted (e.g., digoxin, which has not been shown to be effective in patients with normal ventricular systolic function). [69]

Echocardiography or radionuclide ventriculography can substantially improve diagnostic accuracy in distinguishing between systolic and diastolic dysfunction. [27, 29, 30, 69- 75]

Patients whose symptoms are fully accounted for by an underlying noncardiac condition (see above) or who have previously documented decreased ventricular performance (e.g., recent echocardiogram or contrast ventriculogram) do not require determination of EF.

Although elderly patients with mild symptoms are often managed without measurement of ventricular performance, this practice is discouraged for the following reasons:

· The elderly are the very individuals in whom it may be most difficult to make the diagnosis of heart failure and to determine whether failure is due to systolic or diastolic dysfunction.

· Although mild diuretic therapy may cause little harm in patients with fluid retention of any etiology, use of other medications-such as ACE inhibitors, digoxin, or nitrates-has significant risks and no established benefit unless they are specifically indicated. These agents may even worsen the condition of patients with heart failure secondary to left-ventricular

diastolic dysfunction.

Both echocardiography and radionuclide ventriculography are appropriate measures for the evaluation of left-ventricular performance. Although EF measured by radionuclide ventriculography may have a higher correlation with cineangiography than that measured by echocardiography (r = 0.88 versus r = 0.78, respectively), [76] echocardiography has good reproducibility (r = 0.89) [77] and accuracy for measuring EF (r = 0.78-0.89). [76- 78] The use of quantitative techniques has been found to improve measurement of EF in some studies. [66, 78] However, Stamm et al. found that real-time estimation by the echocardiographer was more accurate than any of several algorithms tested. [77]

In general, the panel considered echocardiography to be the preferred test because of its ability to assess valvular function and left-ventricular hypertrophy, but selection of a diagnostic test should depend on the capabilities of individual clinical centers. Between 8 and 18 percent of patients will have technically inadequate echocardiograms, in which case radionuclide ventriculography should be performed. [79- 81]

Although there are no studies in the literature on the quality of echocardiography and radionuclide ventriculography in community practice, the panel perceives significant quality problems in the performance and interpretation of both tests. When referred to a specialist, patients should be encouraged to bring a video of the actual images of their echocardiogram with them, rather than a written report. In this way, the quality of the study can be determined directly. Advantages and disadvantages of echocardiography and radionuclide ventriculography are summarized in Table 4.

It is important to note that although echocardiography or radionuclide ventriculography is essential for determining the presence and degree of left-ventricular dysfunction, these tests are less useful in determining the etiology of that dysfunction. Specifically, the presence or absence of regional wall motion abnormalities is of limited value in determining whether a patient's disease is due to coronary artery disease or to idiopathic dilated cardiomyopathy. [79, 80, 82, 83] For example, Diaz et al. found that 56 percent of patients with idiopathic dilated cardiomyopathy had regional wall motion abnormalities rather than global hypokinesis. [80] Conversely, 35 percent of patients with coronary artery disease had global hypokinesis without regional wall motion abnormalities.

Similarly, right-ventricular dilatation is not helpful in distinguishing idiopathic dilated cardiomyopathy from ventricular dysfunction due to ischemia or prior MI. [80, 84] Thus, the findings from echocardiography or radionuclide ventriculography should not be used to determine the etiology of a patient's cardiomyopathy or the need for further evaluations of coronary artery disease, such as coronary artery angiography.

Interpretation of Left-Ventricular Function Testing

The majority of patients with heart failure have moderate-to-severe left-ventricular systolic dysfunction and EF's of <35-40 percent. This guideline is directed at the management of such patients. However, patients with symptoms of heart failure and EF's greater than 40 percent may still have heart failure due to left-ventricular diastolic dysfunction, valvular disease, or pericardial disease. The majority of these etiologies will be discernible with echocardiography. A full discussion of the diagnosis and treatment of these conditions is beyond the scope of this guideline, although a few comments on diastolic dysfunction are necessary because of its high prevalence

Determination of Specific Etiologies for Left-Ventricular Systolic Dysfunction

Once left-ventricular dysfunction is confirmed, the results of the history and physical examination should be reviewed to search for clues to potentially treatable causes of heart failure. Additional information should be sought as appropriate. Clinicians should follow up any positive findings with appropriate laboratory testing. Routine use of myocardial biopsy is not warranted. (Strength of Evidence = C.)

The most common causes of left-ventricular systolic dysfunction are coronary artery disease, idiopathic dilated cardiomyopathy, hypertension, and alcohol abuse. The most common potentially reversible cause of heart failure is myocardial ischemia. Therefore, patients should be carefully questioned concerning a history of chest pain or recurring episodes of sudden pulmonary edema suggestive of ischemia. Evaluation of patients with angina is discussed subsequently in the section on revascularization. Alcoholism is important to detect and treat because alcohol may aggravate cardiac dysfunction. [91- 93] Where appropriate, patients should also be asked about cocaine use, and a urine test for cocaine may be helpful in selected patients. Specific treatable etiologies (e.g., sarcoidosis) should be considered when the constellation of systemic findings suggests a diagnosis. Patients with a history of liver disease, unexplained hepatomegaly, diabetes or other endocrine dysfunction, or bronze discoloration of the skin should be evaluated for hemochromatosis with a serum iron level, total iron binding capacity, and ferritin level. An exhaustive search for the etiology of heart failure in a patient without specific findings on history and physical examination is of little value

Table 1--Cardiac Pump Function During and After Acute Hypertensive

Pulmonary Edema *

DHF Compared to SHF

SHF (n = 20) DHF (n = 18) (n = 18) %

Variables During After During After During After

LVEDV, mL 131 138 85 94

LVESV, mL 78 83 36 37

LVSV, mL 53 55 49 57 -7 +3

HR, beats/min 87 77 79 66 -9 -15

LVEF, % 40 40 58 61 +43 +52

CO, L/min 4.6 4.3 3.9 3.8 -15 -12

* Derived from Gandhi et al. (1) Since their article included no HR or

volume data for the SHF group, these data were computed via spreadshhet

from the published DHF and combined DHF-SHF values. To achieve the best

approximation of the original observations (available from the author),

LVEF values were then calculated from the computed volumes, minor

deviations anticipated due to precision/rounding error. LVES = LV

end-systolic volume; LVSV = LV stroke volume; LVEDV = left ventricular

end-diastolic volume.

Table 2--LVEF: Meaningless in Terms of Cardiac

Output Without the Coexisting LVEDV *

Variables Normal SHF DHF-1 DHF-2 SDf

LVEDV, mL 120 250 100 85 200

LVESV, mL 50 200 50 35 130

LVSV, mL 70 50 50 50 70

HR, beats/min 60 60 60 60 60

LVEF, % 60 20 50 60 35

CO, L/min 4.2 3.0 3.0 3.0 4.2

[DELTA]CO, from normal, % 0 -30 -30 -30 0

* Derived from Braunwald et al, (9) whose angiographic volume indexes

are converted here to absolute volumes using nominal body surface

area (1.73 [m.sup.2] and liberal rounding to facilitate interpretation

(but in all cases <2%). DHF-1 = DHF due to mild-to-moderate DDf;

DHF-2 = DHF due to severe DDf; SDf = systolic dysfunctions

without HF; see Table 1 for expansion of abbreviates.

Systolic Dysfunction

Systolic dysfunction refers to impaired ventricular contraction. In chronic heart failure, this is most likely due to changes in the signal transduction mechanisms regulating cardiac excitation-contraction coupling. The loss of cardiac inotropy (i.e., decreased contractility) causes a downward shift in the Frank-Starling curve (Figure 1). This results in a decrease in stroke volume and a compensatory rise in preload (often measured as ventricular end-diastolic pressure or pulmonary capillary wedge pressure). The rise in preload is considered compensatory because it activates the Frank-Starling mechanism to help maintain stroke volume despite the loss of inotropy. If preload did not rise, the decline in stroke volume would be even greater for a given loss of inotropy. Depending upon the precipitating cause of the heart failure, there will be ventricular hypertrophy, dilation, or a combination of the two.

The effects of a loss of intrinsic inotropy on stroke volume, and end-diastolic and end-systolic volumes, are best depicted using ventricular pressure-volume loops (Figure 2). Loss of intrinsic inotropy decreases the slope of the end-systolic pressure-volume relationship (ESPVR). This leads to an increase in end-systolic volume. There is also an increase in end-diastolic volume (compensatory increase in preload), but this increase is not as great as the increase in end-systolic volume. Therefore, the net effect is a decrease in stroke volume (shown as a decrease in the width of the pressure-volume loop). Because stroke volume decreases and end-diastolic volume increases, there is a substantial reduction in ejection fraction (EF). Stroke work is also decreased.

The force-velocity relationship provides insight as to why a loss of contractility causes a reduction in stroke volume (Figure 3). Briefly, at any given preload and afterload, a loss of inotropy results in a decrease in the shortening velocity of cardiac fibers. Because there is only a finite period of time available for ejection, a reduced velocity of ejection results in less blood ejected per stroke. The residual volume of blood within the ventricle is increased (increased end-systolic volume) because less blood is ejected.

The reason for preload rising as inotropy declines is that the increased end-systolic volume is added to the normal venous return filling the ventricle. For example, if end-systolic volume is normally 50 ml of blood and it is increased to 80 ml in failure, this extra residual volume is added to the incoming venous return leading to an increase in end-diastolic volume and pressure.

An important and deleterious consequence of systolic dysfunction is the rise in end-diastolic pressure. If the left ventricle is involved, then left atrial and pulmonary venous pressures will also rise. This can lead to pulmonary congestion and edema. If the right ventricle is in systolic failure, the increase in end-diastolic pressure will be reflected back into the right atrium and systemic venous vasculature. This can lead to peripheral edema and ascites.

Treatment for systolic dysfunction involves the use of inotropic drugs, afterload reducing drugs, venous dilators, and diuretics. Inotropic drugs include digitalis (commonly used in chronic heart failure) and drugs that stimulate the heart via beta-adrenoceptor activation or inhibition of cAMP-dependent phosphodiesterase (used in acute failure). Afterload reducing drugs (e.g., arterial vasodilators) augment ventricular ejection by increasing the velocity of fiber shortening (see force-velocity relationship). Venous dilators and diuretics are used to reduce ventricular preload and venous pressures (pulmonary and systemic) rather than augmenting systolic function directly.

Excitation-Contraction Coupling

Excitation-contraction coupling (ECC) is the process by which an action potential triggers a myocyte to contract. When a myocyte is depolarized by an action potential, calcium ions enter the cell during phase 2 of the action potential through L-type calcium channels located on the sarcolemma. This calcium triggers a subsequent release of calcium that is stored in the sarcoplasmic reticulum (SR) through calcium-release channels ("ryanodine receptors"). Calcium released by the SR increases the intracellular calcium concentration from about 10-7 to 10-5 M. The free calcium binds to troponin-C (TN-C) that is part of the regulatory complex attached to the thin filaments. When calcium binds to the TN-C, this induces a conformational change in the regulatory complex such that troponin-I (TN-I) exposes a site on the actin molecule that is able to bind to the myosin ATPase located on the myosin head. This binding results in ATP hydrolysis that supplies energy for a conformational change to occur in the actin-myosin complex. The result of these changes is a movement ("ratcheting") between the myosin heads and the actin, such that the actin and myosin filaments slide past each other thereby shortening the sarcomere length. Ratcheting cycles occur as long as the cytosolic calcium remains elevated. At the end of phase 2, calcium entry into the cell slows and calcium is sequestered by the SR by an ATP-dependent calcium pump (SERCA, sarco-endoplasmic reticulum calcium-ATPase), thus lowering the cytosolic calcium concentration and removing calcium from the TN-C. To a quantitatively smaller extent, cytosolic calcium is transported out of the cell by the sodium-calcium-exchange pump. The reduced intracellular calcium induces a conformational change in the troponin complex leading, once again, to TN-I inhibition of the actin binding site. At the end of the cycle, a new ATP binds to the myosin head, displacing the ADP, and the initial sarcomere length is restored.

Mechanisms that enhance the concentration of cytosolic calcium increase the amount of ATP hydrolyzed and the force generated by the actin and myosin interactions, as well as the velocity of shortening. Physiologically, cytosolic calcium concentrations are influenced primarily by beta-adrenoceptor-coupled mechanisms. Beta-adrenergic stimulation, as occurs when sympathetic nerves are activated, increases cAMP which in turn activates protein kinase to increase in calcium entry into the cell through L-type calcium channels. Activation of the IP3 signal transduction pathway also can stimulate the release of calcium by the SR through IP3 receptors located on the SR. Furthermore, activation of the cAMP-dependent protein kinase phosphorylates a protein (phospholamban) on the SR that normally inhibits calcium uptake. This disinhibition of phospholamban leads to an increased rate of calcium uptake by the SR. Therefore, beta-adrenergic stimulation increases the force and shortening velocity of contraction (i.e., positive inotropy), and increases the rate of relaxation (i.e., positive lusitropy).

Another potential regulatory mechanism for ECC involves altering the sensitivity of TN-C for calcium. There are investigational drugs that enhance TN-C calcium sensitivity and thereby exert a positive inotropic influence on the heart. One potential downside with these drugs, however, is that enhanced TN-C binding to calcium can reduce the rate of relaxation, thereby causing diastolic dysfunction.

In systolic heart failure, ECC can be impaired at several different sites. First, there can be decreased influx of calcium into the cell through L-type calcium channels (resulting from impaired signal transduction), which decreases subsequent calcium release by the SR. There can also be a decrease in TN-C affinity for calcium, so that a given increase in calcium in the vicinity of the troponin complex has less of an activating effect on cardiac contraction. In some forms of diastolic heart failure, there is evidence that the function of the SR ATP-dependent calcium pump is impaired. This defect would retard the rate of calcium uptake by the SR and reduce the rate of relaxation, leading to diastolic dysfunction.

Signal Transduction Mechanisms (G-Protein and IP3-Linked)

There are several major signal transduction mechanisms found in cells of the cardiovascular system, the most important being the G-protein pathway, IP3 pathway, and the nitric oxide-cyclic GMP pathway. Described below are the G-protein and IP3 pathways found in the heart. Signal transduction mechanisms regulating vascular smooth muscle contraction and relaxation are found elsewhere.

G-proteins are linked to adenylyl cyclase that dephosphorylates ATP to form cyclic AMP (cAMP). Gs activation (e.g., via b-adrenoceptors) increases cAMP, which activates a protein kinase that causes increased gCa++ by direct effects on calcium channels and enhanced release of Ca++ by the sarcoplasmic reticulum in the heart; these actions increase inotropy. Gs-protein activation also increases heart rate. Gi activation (e.g., via adenosine and muscarinic receptors) decreases cAMP and protein kinase activation, and causes increased gK+; activation of the Gi-protein pathway therefore enhances repolarization. Gi-protein activation therefore decreases heart rate and inotropy.

The IP3 pathway is linked to activation of a1-adrenoceptors, angiotensin II (AII) receptors, and endothelin-1 (ET-1) receptors. Increased IP3 stimulates Ca++ release by the sarcoplasmic reticulum in the heart, thereby increasing inotropy.

R, receptor; Gs and Gi, stimulatory and inhibitory G-proteins; AC, adenylyl cyclase; PIP2, phosphatidylinositol 4,5-bisphosphate; IP3, inositol 1,4,5-triphosphate; DAG, diacylglycerol; PK, protein kinase; SR, sarcoplasmic reticulum; a and b , adrenoceptor agonist; M2, muscarinic receptor agonist; A1, adenosine receptor agonist; AII, angiotensin receptor agonist; ET-1, endothelin.

Altered signal transduction mechanisms may be responsible for the loss of inotropy in heart failure.

For example, desensitization of b1-adrenoceptors on the heart will decrease inotropic responses to sympathetic activation. Uncoupling of the b1-adrenoceptor and the Gs-protein would reduce the ability to activate adenylyl cyclase. If the ability of protein kinase A (PK-A) to phosphorylate L-type calcium channels is impaired, then calcium influx into the cell would be reduced, leading to a smaller release of calcium by the sarcoplasmic reticulum. Reduced calcium release would impair excitation-contraction coupling, thereby decreasing inotropy.

Inotropy

Changes in stroke volume can be accomplished by changes in ventricular inotropy (contractility). Changes in inotropy are unique to cardiac muscle. Skeletal muscle, for example, cannot alter its intrinsic inotropic state. Changes in inotropy result in changes in force generation, which are independent of preload (i.e., sarcomere length). This is clearly demonstrated by use of length-tension diagrams in which an increase in inotropy results in an increase in active tension at a given preload. Furthermore, inotropy is displayed in the force-velocity relationship as a change in Vmax; that is, a change in the maximal velocity of fiber shortening at zero afterload. The increased velocity of fiber shortening that occurs with increased inotropy increases the rate of ventricular pressure development. During the phase of isovolumetric contraction, an increase in inotropy is manifested as an increase in maximal dP/dt (i.e., rate of pressure change).

Changes in inotropy alter the rate of force and pressure development by the ventricle, and therefore change the rate of ejection (i.e., ejection velocity). For example, an increase in inotropy shifts the Frank-Starling curve up and to the left (point A to C in Figure 1). This causes a reduction in end-systolic volume and an increase in stroke volume as shown in the pressure-volume loops depicted in Figure 2. The increased stroke volume also causes a secondary reduction in ventricular end-diastolic volume and pressure because there is less end-systolic volume to be added to the incoming venous return. It should be noted that the active pressure curve that defines the limits of the end-systolic pressure-volume relationship (ESPVR) is shifted to the left and becomes steeper when inotropy is increased. The ESPVR is sometimes used as an index of ventricular inotropic state. It is analogous to the shift that occurs in the active tension curve in the length-tension relationship whenever there is a change in inotropy.

Changes in inotropy produce significant changes in ejection fraction (EF). Increasing inotropy leads to an increase in EF, while decreasing inotropy decreases EF. Therefore, EF is often used as a clinical index for evaluating the inotropic state of the heart. In heart failure, for example, there often is a decrease in inotropy that leads to a fall in stroke volume as well as an increase in preload, thereby decreasing EF. The increased preload, if it results in a left ventricular end-diastolic pressure greater than 20 mmHg, can lead to pulmonary congestion and edema. Treating a patient in heart failure with an inotropic drug (e.g., beta-adrenoceptor agonist or digoxin) will shift the depressed Frank-Starling curve up and to the left, thereby increasing stroke volume, decreasing preload, and increasing EF.

Changes in inotropic state are particularly important during exercise. Increases in inotropic state help to maintain stroke volume at high heart rates. Increased heart rate alone decreases stroke volume because of reduced time for diastolic filling, which decreases end-diastolic volume. When the inotropic state increases at the same time, end-systolic volume decreases so that stroke volume can be maintained.

Factors Regulating Inotropy

The most important mechanism regulating inotropy is the autonomic nerves. Sympathetic nerves play a prominent role in ventricular and atrial inotropic regulation, while parasympathetic nerves (vagal efferents) have a significant negative inotropic effect in the atria but only a small effect in the ventricles. Under certain conditions, high levels of circulating epinephrine augment sympathetic adrenergic effects. In the human heart, an abrupt increase in afterload can cause a small increase in inotropy (Anrep effect) by a mechanism that is not fully understood. An increase in heart rate also stimulates inotropy (Bowditch effect; treppe; frequency-dependent inotropy). This latter phenomenon is probably due to an inability of the Na+/K+-ATPase to keep up with the sodium influx at higher heart rates, which leads to an accumulation of intracellular calcium via the sodium-calcium exchanger. Systolic failure that results from cardiomyopathy, ischemia, valve disease, arrhythmias, and other conditions is characterized by a loss of intrinsic inotropy.

In addition to these physiological mechanisms, a variety of inotropic drugs are used clinically to simulate the heart, particularly in acute and chronic heart failure. These drugs include digoxin (inhibits sarcolemmal Na+/K+-ATPase), beta-adrenoceptor agonists (e.g., dopamine, dobutamine, epinephrine, isoproterenol), and phosphodiesterase inhibitors (e.g., milrinone).

Mechanisms of Inotropy

Most of the signal transduction pathways that stimulate inotropy ultimately involve Ca++, either by increasing Ca++ influx (via Ca++ channels) during the action potential (primarily during phase 2), by increasing the release of Ca++

[Richard B the EMT]

Ace, a small suggestion? When you reproduce these admittedly advanced missives into the EMT City strings, click to disable the smileys, otherwise there's distracting smileys where they don't belong.

[Ace844]

Ace, a small suggestion? When you reproduce these admittedly advanced missives into the EMT City strings, click to disable the smileys, otherwise there's distracting smileys where they don't belong.

No problem..."Richard B" I will do so in the future. Thanks

Ace