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Heart Failure with Preserved Ejection Fraction
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     To the Editor: Owan et al.1 and Bhatia et al.2 (July 20 issue) suggest that the rate of survival among patients who have heart failure with preserved ejection fraction may be similar to that among patients with systolic heart failure. Although neither study was designed to identify the specific causes of death in such patients, the potential contribution of pulmonary hypertension should be considered. Both pulmonary hypertension3 and right ventricular function4 have been shown to predict death in patients with systolic heart failure. Despite growing recognition that heart failure with preserved ejection fraction can also lead to pulmonary hypertension, its clinical significance has not been defined. Thus, it would be informative to determine, in existing databases, the prevalence of pulmonary hypertension among outpatients in stable condition who have heart failure with preserved ejection fraction.5,6 Moreover, only by incorporating an assessment of pulmonary hypertension into longitudinal studies of patients with heart failure with preserved ejection fraction will we define the effect of pulmonary hypertension in affecting important clinical outcomes, including death.

    Christopher A. Fiack, M.D.

    Harrison W. Farber, M.D.

    Boston University Medical Center

    Boston, MA 02118

    cfiack@lung.bumc.bu.edu

    References

    Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006;355:251-259.

    Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006;355:260-269.

    Abramson SV, Burke JF, Kelly JJ Jr, et al. Pulmonary hypertension predicts mortality and morbidity in patients with dilated cardiomyopathy. Ann Intern Med 1992;116:888-895.

    Di Salvo TG, Mathier M, Semigran MJ, Dec GW. Preserved right ventricular ejection fraction predicts exercise capacity and survival in advanced heart failure. J Am Coll Cardiol 1995;25:1143-1153.

    Pritchett AM, Mahoney DW, Jacobsen SJ, Rodeheffer RJ, Karon BL, Redfield MM. Diastolic dysfunction and left atrial volume: a population-based study. J Am Coll Cardiol 2005;45:87-92.

    Gottdiener JS, Kitzman DW, Aurigemma GP, Arnold AM, Manolio TA. Left atrial volume, geometry, and function in systolic and diastolic heart failure of persons > or =65 years of age (the Cardiovascular Health Study). Am J Cardiol 2006;97:83-89.

    To the Editor: Bhatia et al. compare the clinical characteristics of the two study groups, but they do not show data on the presence of obstructive sleep apnea in their patients. Obstructive sleep apnea affects 17 to 24% of North American adults.1 Cardiovascular disturbances are the most important complications, causing severe morbidity and death.2 In a recent study by Yaggi et al.,3 obstructive sleep apnea significantly increased the risk of death from any cause, and the increase was independent of other risk factors. The prevalence of obstructive sleep apnea has been reported to be much greater among patients with diastolic heart failure than in the general community.4 Indeed, obstructive sleep apnea has been identified as an independent risk factor for diastolic dysfunction, and treatment with nasal continuous positive airway pressure has had beneficial effects on diastolic variables.5 A careful search for symptoms of sleep apnea should be made in patients with diastolic heart failure in order to treat this sleep disorder correctly, possibly helping to improve the outcomes for this patient population.

    Miguel A. Arias, M.D., Ph.D.

    Complejo Hospitalario de Jaén

    23007 Jaén, Spain

    maapalomares@secardiologia.es

    Alberto Alonso-Fernández, M.D., Ph.D.

    Hospital Universitario Son Dureta

    07014 Palma de Mallorca, Spain

    Francisco García-Río, M.D., Ph.D.

    Hospital Universitario La Paz

    28046 Madrid, Spain

    References

    Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 2002;165:1217-1239.

    Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365:1046-1053.

    Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005;353:2034-2041.

    Chan J, Sanderson J, Chan W, et al. Prevalence of sleep-disordered breathing in diastolic heart failure. Chest 1997;111:1488-1493.

    Arias MA, Garcia-Rio F, Alonso-Fernandez A, Mediano O, Martinez I, Villamor J. Obstructive sleep apnea syndrome affects left ventricular diastolic function: effects of nasal continuous positive airway pressure in men. Circulation 2005;112:375-383.

    To the Editor: Owan et al. and Bhatia et al. convincingly demonstrate that mortality rates are similar among patients with diastolic heart failure and patients with systolic heart failure of similar severity. As mentioned by Aurigemma in his accompanying editorial,1 prevention and early treatment of coronary artery disease and hypertension should ameliorate the effect of these diseases on the incidence and prevalence of diastolic as well as systolic heart failure. Nonetheless, secondary treatments for systolic heart failure (e.g., defibrillators, afterload-reducing agents, and resynchronization therapy) appear to have been so successful because they have specifically targeted the leading causes of death from the disease: pump failure and arrhythmia. Unfortunately, the leading causes of death among patients with diastolic heart failure have not been clearly identified, and knowledge of these causes may well be essential to guide the development of appropriate treatments. In this regard, it would be of interest for Owan et al. and Bhatia et al. to delineate at least the major causes of death in their patients with diastolic heart failure.

    Kenneth M. Kessler, M.D.

    University of Miami School of Medicine

    Miami, FL 33101

    kmichaelkessler@cs.com

    References

    Aurigemma GP. Diastolic heart failure -- a common and lethal condition by any name. N Engl J Med 2006;355:308-310.

    To the Editor: Bhatia et al. and Owan et al. report that diastolic heart failure is a common disorder associated with high rates of morbidity and mortality. Aurigemma suggests that the development of specific, effective management approaches should be a high priority.

    Digoxin was approved by the Food and Drug Administration in 1997 for use in patients with heart failure, irrespective of the ejection fraction,1 primarily on the basis of a significant reduction in the combined end point of hospitalization or death from heart failure during the first 2 years after randomization in the Digitalis Investigation Group (DIG) trial (Table 1).1 We have recently published the results of the ancillary DIG trial in patients with diastolic heart failure.2 During a mean follow-up of 37 months, digoxin did not significantly reduce the risk of death from any cause or hospitalization for cardiovascular causes, as compared with placebo, but it was associated with a trend toward a reduction in the risk of hospitalization for worsening heart failure (hazard ratio, 0.79; 95% confidence interval, 0.59 to 1.04; P=0.09).

    Table 1. Effect of Digoxin on Hospitalization or Death from Heart Failure in the DIG Trial, According to Left Ventricular Ejection Fraction (LVEF).

    Given the high prevalence and morbidity of diastolic heart failure and the lack of a specific and effective therapeutic agent, digoxin may be considered for the treatment of diastolic heart failure, particularly if patients are symptomatic despite the receipt of other therapies or cannot tolerate other therapies.

    Ali Ahmed, M.D., M.P.H.

    University of Alabama at Birmingham

    Birmingham, AL 35294-2041

    aahmed@uab.edu

    Jerome L. Fleg, M.D.

    National Heart, Lung, and Blood Institute

    Bethesda, MD 20892-7936

    Mihai Gheorghiade, M.D.

    Northwestern University

    Chicago, IL 60611-2908

    References

    Lanoxin (digoxin) tablets, USP: full prescribing information. Research Triangle Park, NC: GlaxoSmithKline, 2001.

    Ahmed A, Rich MW, Fleg JL, et al. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary Digitalis Investigation Group trial. Circulation 2006;114:397-403.

    Drs. Owan and Redfield reply: Fiack and Farber emphasize the potential effect of chronic pulmonary venous hypertension due to heart failure with preserved ejection fraction on the pulmonary vasculature. Indeed, pulmonary venous hypertension in patients who have heart failure with preserved ejection fraction can result in clinically significant pulmonary hypertension similar to that observed in many patients with chronic heart failure and reduced ejection fraction. The mechanisms whereby pulmonary venous hypertension causes pulmonary hypertension are well described.1 We agree that the prevalence and prognostic implications of secondary pulmonary hypertension in patients who have heart failure with preserved ejection fraction need to be better defined. According to a preliminary report from our institution, elderly patients with otherwise unexplained dyspnea are increasingly referred to our pulmonary hypertension clinic after echocardiography has shown a normal ejection fraction, the absence of left-sided valvular disease, and clinically significant pulmonary hypertension.2 These older patients frequently have risk factors for heart failure with preserved ejection fraction and a much higher prevalence of elevated pulmonary-capillary wedge pressure when right heart catheterization is performed. Whether such patients have heart failure with preserved ejection fraction and secondary pulmonary hypertension or a primary pulmonary arteriopathy can be difficult to ascertain.1

    Kessler points out that our incomplete understanding of the cause of death in patients who have heart failure with preserved ejection fraction represents an important impediment in the design of effective therapies. The best data regarding the cause of death in such patients were from a post hoc analysis of the DIG trial, in which the cause of death was analyzed according to ejection fraction.3 The analysis suggested that although most patients who had heart failure with preserved ejection fraction died from cardiovascular causes, the rate of death from noncardiovascular causes was higher among patients with normal ejection fraction than among patients with reduced ejection fraction. Regrettably, it is difficult to ascertain the cause of death retrospectively, limiting our ability to address this important issue.

    Ahmed and colleagues suggest that the results of the DIG trial may provide support for the use of digoxin in patients who have heart failure with preserved ejection fraction, because a trend toward reduction in hospitalizations for heart failure was observed with digoxin in the ancillary trial.4 Given the similarly strong trends toward increases in hospitalizations for suspected toxic effects of digoxin and for unstable angina in patients treated with digoxin, the lack of effect on death from any cause or on hospitalization for cardiovascular events or for any cause and the incomplete understanding of the mechanism whereby digoxin might exert a benefit, it may be premature to adopt such a strategy. The guidelines of the American College of Cardiology–American Heart Association Task Force for the management of heart failure conclude that the use of digoxin in patients who have heart failure with preserved ejection fraction is "not well established."5

    Theophilus E. Owan, M.D.

    Margaret M. Redfield, M.D.

    Mayo Clinic and Foundation

    Rochester, MN 55905

    redfield.margaret@mayo.edu

    References

    Shapiro BP, Nishimura RA, McGoon MD, Redfield MM. Diagnostic dilemmas: diastolic heart failure causing pulmonary hypertension and pulmonary hypertension causing diastolic dysfunction. Adv Pulmon Hypertension 2006;5:13-20.

    Shapiro BP, McGoon MD, Redfield MM. Pulmonary hypertension, normal ejection fraction and elevated pulmonary capillary wedge pressure: idiopathic pulmonary arterial hypertension or diastolic heart failure? Circulation 2004;110:Suppl III:III-677.

    Jones RC, Francis GS, Lauer MS. Predictors of mortality in patients with heart failure and preserved systolic function in the Digitalis Investigation Group trial. J Am Coll Cardiol 2004;44:1025-1029.

    Ahmed A, Rich MW, Fleg JL, et al. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary Digitalis Investigation Group trial. Circulation 2006;114:397-403.

    Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult -- summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 2005;112:1825-1852.

    Dr. Liu and colleagues reply: We agree with Fiack and Farber with respect to the potential contribution of pulmonary hypertension to death in patients with heart failure. We did not independently assess pulmonary hypertension in the entire cohort; however, we are reviewing the echocardiograms from a subgroup of these patients to look for the presence of right ventricular hypertension. Many patients who have heart failure with preserved systolic function may have elevated ventricular filling pressures, leading to pulmonary hypertension as an important complication affecting their condition. Interestingly, this may also represent an important therapeutic opportunity.

    Arias et al. mention that obstructive sleep apnea is an important factor in the development and outcomes of both systolic and diastolic heart failure. Our group has conducted studies showing the relation between sleep apnea and ventricular dysfunction and outcomes.1,2 Sleep apnea also contributes to the development of atrial fibrillation, stroke, and hypertension and the worsening of heart failure. Heart failure with preserved systolic function is a heterogeneous disease, and sleep apnea could easily be a contributor to its adverse outcome. Tempering this argument, however, is the sex distribution of the population. Sleep apnea is usually more prevalent in men, whereas in our patient population, preserved systolic function was more common in elderly women.

    We agree with Kessler that identification of the causes of death in patients who have heart failure with preserved systolic function will provide important insight into its pathophysiology. We do not have these data available, but we will be examining this issue in other, related data sets. Because patients with heart failure frequently have complex coexisting conditions, they undoubtedly die from causes other than heart failure alone. However, a large proportion of patients with preserved systolic dysfunction are repeatedly hospitalized for heart failure, as are patients with severe systolic heart failure, and they probably ultimately die of heart failure.

    Finally, Ahmed et al. remind us that digoxin has been approved for the treatment of heart failure, irrespective of the ejection fraction. Although specific treatment strategies for heart failure with preserved systolic function have yet to evolve, the general principles are meticulous fluid management and treatment of the underlying conditions. We concur that digoxin certainly does have a role when patients continue to have symptoms or their condition continues to be unstable despite the use of existing therapies.

    Peter P. Liu, M.D.

    Canadian Institutes of Health Research

    Toronto, ON M5G 2C4, Canada

    peter.liu@utoronto.ca

    Douglas S. Lee, M.D., Ph.D.

    Jack V. Tu, M.D. Ph.D.

    Institute for Clinical Evaluative Sciences

    Toronto, ON M4N 3M5, Canada

    References

    Yan AT, Bradley TD, Liu PP. The role of continuous positive airway pressure in the treatment of congestive heart failure. Chest 2001;120:1675-1685.

    Sin DD, Logan AG, Fitzgerald FS, Liu PP, Bradley TD. Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration. Circulation 2000;102:61-66.