Left ventricular diastolic dysfunction as a cause of congestive heart failure. Mechanisms and management.

OBJECTIVE: To define the mechanisms underlying left ventricular diastolic dysfunction in patients with congestive heart failure and normal systolic function and to identify the patients at risk for this syndrome. STUDY SELECTION: Studies were selected that describe the clinical observations of congestive heart failure with normal systolic function and that provide experimental and clinical insights into the mechanisms responsible for ventricular diastolic dysfunction. DATA SYNTHESIS: Recent studies indicate that a large number of patients (up to 40% in some series) presenting with congestive heart failure have preserved left ventricular systolic function. The factors contributing to altered left ventricular diastolic function include fibrosis, hypertrophy, ischemia, and increased afterload. The latter three factors, alone or in combination, predispose to impaired left ventricular relaxation, an active energy-requiring process. Thus, decreased left ventricular diastolic distensibility (increased diastolic pressure at any level of diastolic volume) may arise not only from altered passive elastic properties stemming from fibrosis or increased muscle mass but also from derangements in the dynamics of ventricular relaxation. RESULTS: In patients with essential hypertension, all four of the above mechanisms may be operative. Considering the prevalence of hypertension in the general population, hypertension appears to be an important underlying factor in many patients with heart failure on the basis of diastolic mechanisms. In the patient presenting with dyspnea and elevated filling pressures, but with a nondilated, normally contracting ventricle, treatment with standard heart failure medications (such as digitalis, diuretics, and vasodilators) is often ineffective and may be deleterious. Such patients may respond more favorably to beta-blockers and calcium-channel blockers. CONCLUSIONS: Diastolic dysfunction should be considered in the patient presenting with heart failure symptoms but with normal systolic function, particularly in hypertensive patients with left ventricular hypertrophy.     

Left ventricular diastolic dysfunction: risks, identification, and treatment

Risk factors of cardiovascular disease, such as hypertension, diabetes, and myocardial infarction, if left untreated, will increase the risk of the development of chronic heart failure. Much is known about the pathophysiology and effective treatments of chronic heart failure from left ventricular systolic dysfunction; however, little clinical trial evidence exists concerning benefits of treating patients with chronic heart failure and preserved systolic function, also known as left ventricular diastolic dysfunction. Rather, an understanding of the pathophysiology and patient signs and symptoms has usually dictated choice of treatments. With the results of ongoing trials, as well as the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Preserved and the Digitalis Investigation Group (DIG) trials, clinical evidence is accumulating to support effective treatments in patients with left ventricular diastolic dysfunction. The focus of this review is to discuss the risks of, identification of, and rationale for therapeutic choices being employed for treating left ventricular diastolic dysfunction and implications from studies that may support these choices.     

Diastolic dysfunction

Opinion statement Heart failure is a leading cause of hospital admissions in North America. Approximately half of patients with symptoms of heart failure have normal or minimally impaired systolic function and are therefore diagnosed, by exclusion, with diastolic dysfunction. The therapy of diastolic dysfunction to date is largely unsatisfactory. There have been few outcome-based clinical trials to guide clinicians, and most treatments have been empirically derived from the data from systolic heart failure studies. In general, acute management consists of central volume reduction with loop diuretics and long-acting nitrates. In some cases improvement in left ventricular filling can be achieved by reducing heart rate, usually with either β blockers or calcium channel blockers. The role of digoxin is unclear and it should be used with caution. Theoretically, it has the capacity to further impair ventricular function, but one of the few trials in diastolic heart failure suggested that it improves symptoms and reduces hospitalization. Renin-angiotensin system blockade is a very attractive therapeutic avenue; angiotensin-converting enzyme inhibitors and angiotensin receptor blockers effectively reduce afterload, induce regression of left ventricular hypertrophy in excess of their blood pressure-lowering effect, and confer survival benefits to patients at high risk for cardiovascular death. Although the results of a recent trial using an angiotensin receptor blocker in patients with primarily diastolic heart failure were unimpressive, renin-angiotensin system blockade should still be considered because of its aforementioned benefits. The long-term management of these patients includes a careful assessment for and treatment of myocardial ischemia, treatment of hypertension, and reduction in left ventricular hypertrophy. For the treatment of ischemia, long-acting nitrates and calcium channel blockers may be particularly useful. The results of new trials in this area are expected soon, and hopefully therapy that directly targets the pathophysiologic pathways of this important disease is on the horizon.     

An update on diastolic dysfunction

Diastolic dysfunction refers to abnormal diastolic filling properties of the left ventricle regardless of whether systolic function is normal or the patient has symptoms. Diastolic heart failure (HF), or more accurately, HF with preserved systolic function, is a distinct clinical entity characterized by the presence of the triad of impaired diastolic function, normal systolic function (left ventricular ejection fraction > 50%), and symptoms of HF. Patients with HF with preserved systolic function are frequently symptomatic from both acute and chronic elevations in left ventricular end-diastolic pressure and/or left atrial pressure.     

Diastolic dysfunction in exercise and its role for exercise capacity

Diastolic dysfunction is frequent in elderly subjects and in patients with left ventricular hypertrophy, vascular disease and diabetes mellitus. Patients with diastolic dysfunction demonstrate a reduced exercise capacity and might suffer from congestive heart failure (CHF). Presence of symptoms of CHF in the setting of a normal systolic function is referred to as heart failure with normal ejection fraction (HFNEF) or, if evidence of an impaired diastolic function is observed, as diastolic heart failure (DHF). Reduced exercise capacity in diastolic dysfunction results from a number of pathophysiological alterations such as slowed myocardial relaxation, reduced myocardial distensibility, elevated filling pressures, and reduced ventricular suction forces. These alterations limit the increase of ventricular diastolic filling and cardiac output during exercise and lead to pulmonary congestion. In healthy subjects, exercise training can enhance diastolic function and exercise capacity and prevent deterioration of diastolic function in the course of aging. In patients with diastolic dysfunction, exercise capacity can be enhanced by exercise training and pharmacological treatment, whereas improvement of diastolic function can only be observed in few patients.     

Heart failure with normal systolic function

Contrary to popular belief, population studies indicate that most elderly patients with heart failure have preserved left ventricular systolic function (i.e., presumed diastolic heart failure). Several normal aging changes may predispose older individuals to diastolic heart failure, including increased hypertrophy and stiffness of the left ventricle, increased vascular stiffness, and decreased cardiovascular reserve. Progress in diastolic heart failure has been hindered by a lack of standard case definition; absence of a readily available, reliable test to quantitate diastolic function; poor understanding of the pathophysiology of heart failure; and lack of data from randomized, controlled, multicenter trials. Typical patients are older women with chronic hypertension, left ventricular hypertrophy, chronic exercise intolerance, and occasional acute exacerbations (pulmonary edema). Although heart failure is a clinical, bedside diagnosis, echocardiography is helpful in differentiating diastolic from systolic heart failure and in ruling out other disorders. Although optimal pharmacologic therapy has not been clarified, control of blood pressure; exercise conditioning; and a multidisciplinary, case management approach seem beneficial.     

Congestive heart failure in patients with normal left ventricular systolic function: a manifestation of diastolic dysfunction.

Diastolic dysfunction is a relatively common problem that may be mild and asymptomatic or may present with congestive heart failure and severe disabling symptoms. It is frequently due to coronary artery disease or left ventricular hypertrophy and it is especially common in the older population. The pathophysiology is related to increased left ventricular passive stiffness and impaired or slowed myocardial relaxation. Patients with diastolic dysfunction are best treated with calcium channel blocking agents or beta-blocking agents (drugs that are generally avoided in patients with significant systolic dysfunction). Most treatment is based on symptomatic relief, and therefore periods of cautious trial and error are the rule. Congestive symptoms are treated with agents that reduce pulmonary venous pressure; in general positive inotropic agents and arterial vasodilators are not useful in heart failure that is due to diastolic dysfunction.     

The clinical quandary of left and right ventricular diastolic dysfunction and diastolic heart failure

Summary

Diastolic heart failure is a common clinical entity that is indistinguishable from systolic heart failure without direct evaluation of left ventricular function. Diastolic heart failure is a clinical diagnosis in patients with signs and symptoms of heart failure but with preserved left ventricular function and normal ejection fraction, and is often seen in patients with a long-standing history of hypertension or infiltrative cardiac diseases. In contrast, diastolic dysfunction represents a mechanical malfunction of the relaxation of the left ventricular chamber that is primarily diagnosed by two-dimensional transthoracic echocardiography and usually does not present clinically as heart failure. The abnormal relaxation is usually separated in different degrees, based on the severity of reduction in passive compliance and active myocardial relaxation. The question whether diastolic dysfunction ultimately will lead to diastolic heart failure is critically reviewed, based on data from the literature. Treatment recommendations for diastolic heart failure are primarily targeted at risk reduction and symptom relief. Currently, few data only are reported on diastolic dysfunction and its progression to systolic heart failure.     

Diastolic heart failure: old story, new concepts

Diastolic heart failure refers to a clinical syndrome characterised by symptoms and signs of congestive heart failure, with a normal or subnormal left ventricular (LV) systolic function associated with alterations in LV diastolic function. Diastolic dysfunction is a pathological condition during which the LV is unable to accept a volume of blood coming back from the lungs appropriate to maintain its stroke volume under normal filling pressure. Three eventually associated mechanisms are responsible for such dysfunction: impaired LV relaxation, increased LV stiffness and loss of normal atrial function. Prevention of LV hypertrophic remodelling should decrease the incidence of diastolic heart failure.     

Aspects of the Use of Angiotensin-Converting Enzyme Inhibitors and Calcium Antagonists in Treatment of Heart Failure in the Older Patient

The syndrome of congestive heart failure may result from either systolic or diastolic dysfunction of the left ventricle. Diastolic left ventricle dysfunction is particularly common in the geriatric age group, and is associated with left ventricular hypertrophy resulting from aging and hypertension. The clinical differentiation of these two patterns is important in understanding the pathophysiologic process and in selecting appropriate therapy. Angiotensin-converting enzyme (ACE) inhibitors are useful in systolic dysfunction, both in improving clinical manifestations of reduced cardiac output and in actually prolonging survival. ACE inhibitors are also beneficial in diastolic heart failure by promoting regression of left ventricular hypertrophy, thus improving diastolic physiological function. Calcium antagonists improve diastolic function by reducing blood pressure of hypertensive subjects, reducing left ventricular mass, and theoretically, by facilitating the energy-dependent transport of calcium ions from the actin-myosin complex into the sarcoplasmic reticulum. However, because of the negative inotropic properties of the calcium antagonists, they should be used cautiously, if used at all, in patients with significant systolic dysfunction, at least until the results of clinical trials using these drugs in systolic congestive heart failure are available.     

Treatment of hypertension in heart failure with preserved ejection fraction: role of the kidney

Heart failure can present clinically as primarily diastolic or systolic dysfunction or both. There is an increasing awareness that heart failure can occur in the presence of a normal left ventricular ejection fraction. Heart failure with normal left ventricular ejection fraction is frequently referred to as diastolic heart failure because of the presence of diastolic left ventricular dysfunction evident from impaired left ventricular relaxation. This article focuses on the treatment of hypertension and the role the kidney plays in selecting appropriate agents.     

Beurteilung der diastolischen Herzinsuffizienz

Diastolic heart failure, also known as heart failure with preserved left ventricular ejection fraction (HF-pEF), is responsible for approximately 50 % of all heart failure cases. According to current guidelines the diagnosis HF-pEF requires three criteria: (1) signs or symptoms of heart failure, (2) presence of a normal left ventricular ejection fraction and (3) evidence of diastolic dysfunction. Echocardiography is the diagnostic modality of choice, especially after ruling out other causes of dyspnea, such as pulmonary diseases, heart rhythm disturbances and volume overload. Important echocardiographic parameters for the assessment of diastolic function are atrial dimensions, myocardial mass, mitral inflow pattern, pulmonary vein flow, propagation velocity of mitral inflow and the tissue Doppler of the mitral annulus. Nevertheless, a complete echocardiographic examination should be performed in every patient with heart failure. In general, diastolic dysfunction is frequently associated with increased atrial diameter and left ventricular hypertrophy. In advanced stages pulmonary hypertension can be present. A robust method for evaluation of systolic function in patients with diastolic dysfunction is crucial. The mitral inflow pattern provides various parameters to describe diastolic function (E/A ratio, deceleration time, isovolumetric relaxation time). In case of difficulties to separate a normal from a pseudonormal mitral inflow pattern the Valsalva maneuver can be used. Another valuable parameter for this differentiation is the duration of the backward flow in the pulmonary veins in contrast to forward flow over the mitral valve. Tachycardia or atrial fibrillation is a major problem for grading of diastolic function; however, in patients with atrial fibrillation E/e’ is a well-established parameter. In summary, this review provides a detailed overview and discussion of the established and newer echocardiography techniques for the evaluation of diastolic function and provides an algorithm for the assessment of diastolic dysfunction in everyday routine.     

"Pure" diastolic dysfunction is associated with long-axis systolic dysfunction. Implications for the diagnosis and classification of heart failure

AIMS: To investigate regional systolic function of the left ventricle, to test the hypothesis that "pure" diastolic dysfunction (impaired global diastolic filling, with a preserved ejection fraction > or = 50%) is associated with longitudinal systolic dysfunction. METHODS AND RESULTS: One hundred thirty subjects (31 patients with asymptomatic diastolic dysfunction, 30 with diastolic heart failure, 30 with systolic heart failure; and 39 age-matched normal volunteers) were studied by conventional and tissue Doppler echocardiography. Global diastolic function was assessed using the flow propagation velocity, and by estimating left ventricular filling pressure from the ratio of transmitral E and mitral annular E(TDE) velocities (E/E(TDE)); and global systolic function by measurement of ejection fraction. Radial and longitudinal functions were assessed separately from posterior wall and mitral annular velocities. Global and radial systolic function were similar in patients with "pure" diastolic dysfunction and normal subjects, but patients with either asymptomatic diastolic dysfunction or diastolic heart failure had impaired longitudinal systolic function (mean velocities: 8.0+/-1.2 and 7.7+/-1.5 cm/s, respectively, versus 10.1+/-1.5 cm/s in controls; p<0.001). In subjects with normal ejection fraction, global diastolic function correlated with longitudinal systolic function (r=0.56 for flow propagation velocity, and r=-0.53 for E/E(TDE) ratio, both p<0.001), but not with global systolic function. CONCLUSION: Worsening global diastolic dysfunction of the left ventricle is associated with a progressive decline in longitudinal systolic function. Diastolic heart failure as conventionally diagnosed is associated with regional, subendocardial systolic dysfunction that can be revealed by tissue Doppler of long-axis shortening. Diagnostic algorithms and definitions of heart failure need to be revised.     

Right ventricular failure in patients with preserved ejection fraction and diastolic dysfunction: an underrecognized clinical entity

It is well recognized that patients with severe left ventricular (LV) systolic dysfunction develop pulmonary venous hypertension or postcapillary pulmonary hypertension, which leads to an increase in pulmonary vascular resistance (PVR) and right ventricular (RV) systolic failure. It is often underrecognized, however, that patients with heart failure with preserved LV ejection fraction and diastolic dysfunction may also develop postcapillary pulmonary hypertension with elevated PVR leading to RV systolic failure. This form of biventricular failure is a result of diastolic failure on the left in patients with preserved LV ejection fraction and systolic failure on the right. At this time, there are no randomized trials or guidelines addressing the management of patients with diastolic heart failure with and without resultant RV failure. The authors review the pathophysiology, clinical presentation, and suggested treatment of this underrecognized clinical entity.     

Modern evaluation of left ventricular diastolic function using Doppler echocardiography

The evaluation of left ventricular (LV) diastolic function is an essential component of the echocardiographic examination for dyspneic patients with impaired or preserved LV systolic function. Doppler echocardiography in combination with two-dimensional echocardiographic findings can assist the diagnosis of underlying cardiac dysfunction, give an estimate of LV filling pressures, guide heart failure treatment, and provide important prognostic information. This article reviews the essentials of modern Doppler assessment of diastolic function and highlights recent updates, areas of controversy, and future applications.     

Is 'diastolic heart failure' a diagnosis of exclusion? Echocardiographic parameters of diastolic dysfunction in patients with heart failure and normal systolic function

Background: Diastolic heart failure (DHF) is reported to account for 30–50% of heart failure presentations, but its prevalence in the absence of overt coronary disease is unclear. Diastolic heart failure is usually defined by exclusion (heart failure with normal left ventricular (LV) systolic function), and few studies have sought a specific diagnosis of diastolic dysfunction. The objective of the present study was to determine the prevalence of isolated DHF and characterise LV diastolic function in patients without clinical evidence of coronary disease, who were referred for LV function assessment.

Methods: Among 938 consecutive patients referred for assessment of LV function, diastolic dysfunction was sought in patients with clinical heart failure, normal systolic function, and no valvular or coronary disease. The evaluation was based on measurement of early (E) and late (A) transmitral velocities and E wave deceleration time (DT). Pulmonary vein systolic, diastolic and atrial reversal velocities were used to differentiate pseudonormal filling in patients with normal E/A and DT.

Results: Normal LV systolic function was present in 331 patients (35%), of whom 53 (6%) met criteria for a clinical diagnosis of DHF. Diastolic dysfunction was confirmed by echocardiography in 38 patients (72% of clinical DHF patients), of whom 27 had impaired LV relaxation, 10 had pseudonormal filling, and one had restrictive filling. Diastolic function was normal in 13 and indeterminate in two patients. Pseudonormal or restrictive LV filling were more prevalent in patients with acute heart failure (7/20, P < 0.05).

Conclusions: Carefully defined, isolated DHF is uncommon, but most of these patients demonstrate echocardiographic evidence of diastolic dysfunction.     

Diastolic function in hypertension

Diastolic dysfunction in patients with hypertension may present as asymptomatic findings on noninvasive testing, or as fulminant pulmonary edema, despite normal left ventricular systolic function. Up to 40% of hypertensive patients presenting with clinical signs of congestive heart failure have normal systolic left ventricular function. In this article we review the pathophysiologic factors affecting diastolic function in individuals with diastolic function, current and emerging tools for measuring diastolic function, and current concepts regarding the treatment of patients with diastolic congestive heart failure.     

Hypertension and diastolic heart failure

In patients with hypertension, pressure overload leads to left ventricular hypertrophy (LVH), myocardial fibrosis, and impaired diastolic filling without systolic dysfunction. Presently, diastolic heart failure accounts for about 50% of the heart failure population. Fatigue, dyspnea, reduced exercise tolerance, and peripheral edema are common presenting complaints. As a group, patients with diastolic heart failure are older and predominantly female. Diuretics are effective for treating congestive symptoms. β Blockers and heart rate-lowering calcium blockers show benefit in smaller studies but have not been evaluated in definitive clinical trials. Renin-angiotensin-aldosterone system blockers reduce blood pressure, LVH, and myocardial fibrosis; however, long-term studies with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers demonstrate little effect on symptoms or survival, and inconsistent effects on heart failure hospitalization. At present, evidence-based treatment includes antihypertensive therapy to reduce progression from hypertension to heart failure. In patients with established heart failure, diuretics and other empiric treatments are used to control symptoms.     

Left ventricular function at rest and during Raynaud's phenomenon in patients with scleroderma

We evaluated left ventricular function in 10 scleroderma patients with signs and symptoms suggestive of congestive heart failure. M-mode and two-dimensional echocardiography demonstrated normal to increased systolic function in all patients. The presence of pulmonary venous congestion on the chest radiograph was not useful in assessing left ventricular systolic function. Five of nine patients with normal to increased left ventricular ejection fraction (LVEF) had increased cardiothoracic ratios and increased pulmonary vascular markings. Left ventricular hypertrophy was associated with a worse New York Heart Association functional class, more pulmonary vascular congestion, and greater left atrial size. In the presence of normal systolic function and ventricular hypertrophy, diminished left ventricular diastolic compliance may account for the cardiac dysfunction in these patients. Cold pressor testing induced peripheral Raynaud's phenomenon in nine of nine patients; however, no ST segment changes or chest pain was provoked. In seven of nine patients there was no abnormal fall in LVEF. The mechanism for the fall in ejection fraction seen in two patients may be related to an increase in afterload or myocardial ischemia secondary to coronary atherosclerosis. We found little to suggest that a myocardial Raynaud's phenomenon affects left ventricular perfusion or systolic function. Clinical signs and symptoms of congestive failure as well as chest radiographs are poor indicators of impaired systolic function in scleroderma patients. Based on these findings, it appears that evaluation of left ventricular systolic function should include echocardiographic or angiographic study before such patients are treated for heart failure with inotropic agents.     

Utility of B-natriuretic peptide levels in identifying patients with left ventricular systolic or diastolic dysfunction

PURPOSE: Although echocardiography is important for making the diagnosis of left ventricular dysfunction, its cost and lack of availability limit its use as a routine screening test. B-Natriuretic peptide levels accurately reflect ventricular pressure, and preliminary studies with a rapid assay have found that levels are sensitive and specific for diagnosing heart failure in patients with dyspnea. We hypothesized that B-natriuretic peptide levels obtained through the use of a rapid assay should correlate with echocardiographic abnormalities of ventricular function. SUBJECTS AND METHODS: We studied 400 patients who were referred for echocardiography at the San Diego Veteran's Healthcare System between June and August 2000 to evaluate ventricular function. B-natriuretic peptide levels were measured by a point-of-care immunoassay; cardiologists assessing left ventricular function were blinded to the assay results. Patients were grouped into those with normal ventricular function, systolic dysfunction only, diastolic dysfunction only, and both systolic and diastolic dysfunction. RESULTS: Mean (+/- SD) B-natriuretic peptide concentration was 416 +/- 413 pg/mL in the 253 patients diagnosed with abnormal left ventricular function, compared with 30 +/- 36 pg/mL in the 147 patients with normal left ventricular function. Patients with both systolic and diastolic dysfunction had the highest levels (675 +/- 423 pg/mL). The area under the receiver operating characteristic (ROC) curve for B-natriuretic peptide levels to detect any abnormal echocardiographic finding was 0.95 (91% confidence interval: 0.93 to 0.97). B-Natriuretic peptide levels were unable to differentiate systolic vs. diastolic dysfunction. In patients with symptoms of heart failure and normal systolic function, B-natriuretic peptide levels >57 pg/mL had a positive predictive value of 100% for diastolic abnormalities. CONCLUSIONS: A simple, rapid test for B-natriuretic peptide levels can reliably predict the presence or absence of left ventricular dysfunction on echocardiogram. For some patients, a normal level may preclude the need for echocardiography.