Understanding diastolic dysfunction

The primary therapeutic goal in treating diastolic heart failure is to restore physiologic balance using symptom-mediated therapy. Pharmaceutical therapy used for systolic dysfunction may actually be harmful.

Vishali Chand, PA-C

Vishali Chand is a PA working in family practice and nephrology in Stockton, Calif. She has indicated no relationships to disclose relating to the content of this article.

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Congestive heart failure (CHF) is an inability of the heart to provide adequate forward output at normal filling pressures to meet tissue perfusion and oxygenation requirements.¹ There are two distinct types of heart failure (HF), left ventricular systolic dysfunction (LVSD) and diastolic dysfunction (DD) (see Table 1). LVSD is impaired cardiac contractility with a reduced left ventricular ejection fraction (LVEF) and is associated with cardiac enlargement and loss of functional myocardial mass.² As venous return and atrial pressure increase, cardiac output proportionately increases until further increments overload the heart.

In DD, however, the ejection fraction remains within normal limits. The ventricle is unable to accept blood at a low ventricular pressure, causing an accompanying delay in filling.³ Atrial pressure increases to compensate for delayed filling, leading to pulmonary or systemic congestion. DD occurs in isolation or secondary to underlying pathology.

Frequently misdiagnosed, DD is difficult to identify in the compensated state because it often accompanies systolic dysfunction (SD), and almost all baseline subtleties will resolve with volume and BP control.⁴ Distinguishing DD from SD is essential for implementing appropriate management, especially because optimal therapy for one condition may aggravate the other.⁵  

Epidemiology

CHF in the United States is widespread and costly, both financially and psychologically. More than 4.5 million people have CHF, with more than 550,000 new cases diagnosed each year.⁶ Expenses associated with the disease are up to $40 billion annually. CHF is the leading cause of hospitalization in persons older than 65 years, with an annual admission rate higher than 875,000.⁶ More than two thirds of cases of CHF are attributed to SD. However, up to 30% of patients with CHF have DD, most often secondary to LV hypertrophy (LVH) and systemic hypertension.⁷ The total cost for DD is now more than $10 billion annually.⁶

DD is a relatively common disorder that may be clinically silent or may produce serious morbidity and mortality. Often called the “senescent heart,” it primarily affects the elderly, particularly women.⁸ Total mortality in DD exceeds that in SD.⁸ A recent meta-analysis of more than 19,000 Medicare beneficiaries hospitalized with CHF found that 35% had preserved systolic function and 79% were women.⁹ The mortality rate is 50% lower for patients with stable DD than for those with stable SD. The most effective way to control morbidity and mortality in DD is to understand the pathophysiologic mechanisms, recognize early symptoms, and initiate primary treatment.  

Etiology

Normal diastolic function relies on the ability of the ventricle to pump blood forcefully during systole and to adequately fill at low pressures during diastole.² Diastole occurs after the myocardium contracts in systole while the aortic valve is closed and the mitral valve is open. During diastole, the left ventricle, left atrium, and pulmonary veins form a common chamber continuous with the pulmonary capillary bed (see Figure 1).¹⁰ In late diastole, the ventricle is most compliant and easily distensible, offering minimal resistance to ventricular filling over a normal volume range.¹⁰   

When relaxation and compliance are compromised in DD, ventricular filling is impaired, requiring higher diastolic pressures. The left atrium and pulmonary vein pressures increase to allow filling of a normal volume and, in doing so, produce decreased cardiac output despite normal left ventricular (LV) systolic function.¹⁰ The ventricular filling pressures increase to maintain cardiac output and cause a subsequent increase in atrial pressures. The result is increased pulmonary capillary wedge pressure and classic symptoms of CHF.

Although research into the pathogenesis of DD is lacking, several theories have been proposed. One is that intrinsic myocardial mechanisms such as impaired dynamic relaxation and increased passive stiffness, along with extrinsic factors, play a role in the development of DD, as further delineated in Table 2.¹¹  

Clinical manifestations

Symptoms of DD are neither specific nor distinct from those of LVSD. A Mayo Clinic survey in 2000 evaluated 2,042 subjects older than 45 years and reported that asymptomatic DD is more common than symptomatic disease.⁶ When symptoms do occur, the most common is dyspnea, generally exhibited as a change in exercise tolerance. Orthopnea and paroxysmal nocturnal dyspnea indicate worsening disease. The patient’s spouse may also report apnea or Cheyne-Stokes breathing in the patient at night. Hypoalbuminemia secondary to low colloid osmotic pressure can also worsen states of dyspnea. Because the symptoms of diastolic HF are nonspecific and are found in other cardiac and in noncardiac disorders, an accurate initial diagnosis of CHF is important. A detailed history and physical examination are essential. As many as half the diagnoses of HF made in the primary care setting may be wrong.¹² Incorrect diagnoses may be related to etiologic limitations such as underlying pulmonary disease, obesity, or unrecognized reversible ischemia. Noncardiac causes of dyspnea should be ruled out through pulmonary function and cardiopulmonary exercise testing.

Because the clinical diagnosis of CHF is less accurate in women, the elderly, and obese persons, the European Society of Cardiology proposed diagnostic guidelines that would require objective evidence of LV dysfunction.¹³ The American Medical Association (AMA), however, states that the diagnosis of CHF is clinical and should not be based on the LVEF because this can create a clinical bias in diagnosis, resulting in a systematic and serious underestimation of DD.¹⁴ The AMA says that the first step in diagnosing DD is to establish a diagnosis of CHF based on signs and symptoms, the results of laboratory and radiology studies, and a typical clinical response to treatment with diuretics.

Examination

Diffuse crackles are usually noted during the pulmonary examination and may indicate a pleural or pericardial effusion. The cardiovascular examination may elicit either an S₃ or S₄ gallop. An S₃ gallop indicates a transition from a compensated to a decompensated state with elevated LV filling pressures. An S₄ gallop indicates preserved left atrial pressure and prominent atrial contribution to LV filling secondary to a stiff ventricle. Jugular venous distention (with or without hepatojugular reflux) and abnormal BP response to the Valsalva maneuver indicate venous congestion. In DD, pulsus alternans (reduced proportional pulse pressure) may be present.

Patients with DD have difficulty tolerating certain types of hemodynamic stress and may present with an acutely elevated BP, atrial fibrillation, tachycardia, or pleuritic pain associated with ischemia. Many people with DD also manifest unusual weight gain, ascites, and pedal edema due to systemic congestion from pulmonary overload. In patients with severe, longstanding CHF, cardiac cachexia may imitate the cachexia of disseminated malignant disease. 

Laboratory tests

The measurement of atrial peptides or brain natriuretic peptides (BNP) is a tool to distinguish CHF from other causes of acute dyspnea or chronic obstructive pulmonary disease, but it cannot distinguish DD from SD. In one report, 294 patients with DD were referred for echocardiography; a plasma BNP level greater than 62 pg/mL had a sensitivity of 85% and a specificity of 83% for diagnosing DD.¹⁵ In this study, the mean plasma BNP level was 286 pg/mL, significantly higher than in the control group.¹⁵ 

Diagnostic tests

An ECG is important for ruling out LVH or atrial fibrillation. Consider ordering a chest film for evidence of pulmonary venous congestion, left atrial enlargement, LVH, or pericardial calcification. Normal systolic function should be documented by echocardiography or radionuclide scanning to measure LVEF. Transthoracic echocardiography will distinguish DD from SD by confirming a nondilated ventricle with preserved systolic function through ventricular wall thickness and motion measurements. Echocardiography helps identify LVH, valvular heart disease, pericardial disease, and ventricular EF. For diagnosing DD, echocardiography will show a characteristic restrictive abnormal inflow across the mitral valve (open in diastole): early rapid ventricular filling (E wave) being greater than atrial systolic filling (A wave), or impaired diastolic relaxation with a ratio of E wave to A wave less than 0.6.¹⁶

Many times, Doppler ultrasonography (US) is used in conjunction with echocardiography to examine extrinsic diastolic abnormalities of impaired relaxation. Tissue Doppler imaging (TDI) is also used in conjunction with Doppler US to accurately assess LV relaxation, compliance, and contraction times via measurements of the atrial boost pump function and blood flow velocities into the left ventricle.^3,17

The gold standard for definitive diagnosis is cardiac catheterization. However, patients with CHF cannot always undergo this invasive procedure, particularly if they have already been clinically stabilized with diuretics, which can lead to inaccurate measurements. Thus, current diagnostic standards for DD utilize echocardiography with Doppler US. According to AMA guidelines, if patients with CHF have a normal LVEF in the absense of primary volume overload conditions and noncardiac causes of symptoms, the HF is due to DD.¹⁸  

Treatment and prognosis

Stratifying patients with CHF into those with SD and DD has been suggested because of the important therapeutic and prognostic differences between SD and DD.² Prognosis is not well defined but is largely dependent on whether the patient is symptomatic. For symptomatic patients, population-based studies such as V-HeFT (Vasodilator-Heart Failure Trial), the Framingham studies, and the Cardiovascular Health Study showed a better short-term prognosis for those with DD than for those with LVSD.⁵ V-HeFT also demonstrated that compared with systolic HF, diastolic HF appears to be associated with decreased morbidity and mortality; annual mortality in patients with DD was less than half that in patients with a reduced LVEF.⁵ An evaluation of 413 hospitalized patients also exhibited a lower relative risk of CHF due to DD than to SD.¹⁹ Ultimately, a patient with DD who receives proper medical management will have a more favorable outcome than one with SD.^5,6

Principles of treatment

No randomized, double-blind, placebo-controlled, multicenter trials have been performed in patients with DD. Because validated diagnostic criteria have not yet been established, nonpharmacologic and pharmacologic approaches are not proven. Therefore, treatment guidelines remain empiric, based on clinical investigations in small patient groups and underlying pathophysiologic disease.^6,11 The two main treatment goals are to reduce symptoms and improve prognosis by eliminating or reducing underlying pathology (see Table 3). Many of the medications used to treat SD can also be used for DD. However, the rationale and dosing regimen are unique to the diagnosis: optimal therapy for one condition may aggravate the other.⁵

Reducing symptoms

Because dyspnea is the most common manifestation of DD, the primary treatment goal is to reduce pulmonary congestion by decreasing pulmonary venous pressure. Diuretics reduce diastolic volume by decreasing total blood volume, whereas nitrates reduce diastolic pressure by increasing venous capacitance. In DD, higher filling pressures are needed to maintain cardiac output; vigorous diuresis can lead to relatively large changes in ventricular diastolic pressure. Excessive preload reduction can be extremely dangerous in patients with aortic stenosis or hypertrophic cardiomyopathy and will manifest as signs of hypotension—weakness, dizziness, and syncope—all representative of ventricular underfilling.

Improve exercise capacity Many patients with DD have a markedly limited exercise tolerance with symptoms of fatigue and dyspnea. Agents such as beta-blockers (BBs), calcium channel blockers (CCBs), and renin-angiotensin axis blockaders (either ACE inhibitors or angiotensin-receptor blockers [ARBs]) modify the hemodynamic response to exercise and improve exercise capacity in patients with DD.

Control heart rate Used individually or in combination as first-line agents, BBs and CCBs can help to maintain rate control.²⁰ In several small studies, BBs improved survival for patients with DD who have idiopathic dilated cardiomyopathy or who have had an acute MI.²⁰ BBs increase the time available for ventricular filling and coronary flow in diastole, thereby reducing myocardial oxygen demand.²¹ The decrease in heart rate also provides additional time for calcium to exit from myocytes, reversing the cellular calcium overload characteristic of DD.²² Furthermore, patients who are well compensated can quickly decompensate with atrial fibrillation due to the loss of utilization of the atrial kick. BBs or CCBs can be used along with therapeutic anticoagulation to maintain normal sinus rhythm.

Targeting underlying disease

The mainstay of treatment of isolated DD is uncertain. Studies are evaluating the use of ACE inhibitors and ARBs. Inhibition of the renin-angiotensin system reverses interstitial collagen deposition; fibrosis is prevented and distensibility of the ventricle is improved as myocardial stiffness diminishes.²³ In patients with LVH and hypertension, the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study showed that losartan reduced cardiovascular complications better than atenolol did.²⁴ Additionally, losartan has been associated with greater regression of myocardial fibrosis and subsequent reduction in ventricular stiffness.²⁵ Regression of LVH secondary to hypertension is an important therapeutic goal since it is one of the most common underlying causes of DD. According to AMA guidelines, in patients with DD and LVH secondary to hypertrophic cardiomyopathy, ischemia, or coronary disease, treatment should be aimed at maintaining an appropriate heart rate, relieving pericardial strain, and increasing filling time. Although additional studies are being conducted with ARBs, first-line therapy for DD continues to be CCBs or BBs.

Some treatments used for SD are not beneficial in patients with DD and may prove harmful. Positive inotropic agents should generally be avoided because LVEF is preserved in DD and these agents can therefore worsen symptoms. Digoxin may induce ischemia, tachycardia, and arrhythmias; digitalis may also exacerbate the relative calcium overload during diastole.²⁶ Arterial vasodilators such as hydralazine and alpha-adrenergic receptor blockers such as prazosin are both likely to worsen diastolic function by the sympathetic response of an increased contractile force or heart rate.

Prevention

Clinicians should first educate themselves about how to distinguish between SD and DD, placing emphasis on how to control risk factors and comorbid conditions. The next step is to educate patients, who should be able to recognize warning signs such as exercise intolerance and weight gain. Obtaining baseline weight is crucial, and patients should be encouraged to conduct daily weight checks, as a reported weight gain of 1 to 2 kg over 2 to 3 days is an early sign of fluid overload.²⁷

Modifying risk factors may prevent exacerbations and make diagnosis easier. Hypertension and coronary disease must be managed with appropriate medications that will not contribute to excessive preload reduction and changes in ventricular diastolic pressure. Patients should restrict sodium and fluid intake, refrain from smoking, decrease alcohol consumption, and avoid NSAIDs. Maintaining a normal body mass index and exercising regularly to control edema can be beneficial and prevent exacerbations of HF symptoms. With patients who have a history of atrial fibrillation or tachycardia, efforts should be made to reestablish normal sinus rhythm or maintain heart rate control.

Conclusion

The confidence with which a clinician makes a diagnosis of DD varies, depending on the quantity and quality of the supportive clinical and laboratory evidence. This is an insidious disease and a major contributor to morbidity, mortality, hospitalization, and medical costs in the United States. Making the diagnosis requires three sequential steps: establish a diagnosis of CHF; document normal LV systolic function by echocardiography with TDI; and determine the most likely etiology for DD. Measuring BNP levels will help to substantiate the diagnosis.⁴ Once the diagnosis of DD is established, the principal etiologic mechanism can be determined so that treatment can be targeted appropriately.   •

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