Diastolic Heart Failure in the Elderly and the Potential Role of Aldosterone Antagonists
The overall incidence of heart failure increases with age, affecting up to 10% of people >65 years of age. Diastolic heart failure is also age-dependent, increasing from <15% in middle-aged patients to >40% in patients ≥;70 years of age. Elderly patients usually have other co-morbid conditions such as hypertension, diabetes mellitus, coronary artery disease and atrial fibrillation that can adversely affect the diastolic properties of the heart.
The clinical manifestations of diastolic heart failure are similar to those of systolic heart failure. In practice, the diagnosis is generally based on the finding of typical symptoms and signs of heart failure with preserved left ventricular ejection fraction and no valvular abnormalities on echocardiography.
Altered ventricular relaxation and abnormal ventricular filling are the hallmarks of diastolic heart failure. Cardiac fibrosis and cellular disarray lead to the alterations in the diastolic properties of the heart. Diffuse foci of fibrosis in the myocardium have been reported with advancing age. Aldosterone has been shown to play a crucial role in the development of cardiac fibrosis via a direct effect on the mineralocorticoid receptors within the myocardium.
Unlike the situation with treatment of systolic heart failure, few clinical trials are available to guide the management of patients with diastolic heart failure. In the absence of controlled clinical trials, patient management is based on control of the physiological factors (blood pressure, heart rate, blood volume and myocardial ischaemia) that are known to exert important effects on ventricular relaxation. Aldosterone antagonists inhibit the deposition of collagen matrix in the myocardium, thereby targeting the basic pathophysiological mechanism of diastolic dysfunction. Thus, they appear to represent a promising therapeutic approach for this condition. Currently, only small clinical trials supporting this therapy are available and large clinical trials evaluating long-term outcomes in diastolic dysfunction are therefore needed.
Heart failure is a common cardiovascular disorder in the elderly. Its incidence increases with age, affecting up to 10% of people >65 years of age.[1,2] In the US, heart failure is one of the most common diagnoses at discharge among Medicare beneficiaries. A recent estimate suggested that the total cost of heart failure-related care in the US could be as high as $US27.9 billion. Although heart failure can occur as a result of any functional or structural cardiac disorder that leads to an abnormality in systolic and/or diastolic performance, the proportion of patients with heart failure and a relatively normal or preserved systolic function (left ventricular ejection fraction [LVEF] >50%) increases with advancing age. Approximately 30–50% of elderly patients with heart failure have preserved LV systolic function, and the majority of these patients have impairment of diastolic function, so called diastolic heart failure (DHF).[4, 5, 6, 7, 8, 9, 10, 11] DHF is a serious condition. The overall mortality rate of DHF is probably slightly lower than that of systolic heart failure (SHF) but the morbidity of the two conditions is similar.[11, 12, 13] Given the ever-increasing elderly segment of our population, DHF is likely to become an even larger health and socioeconomic problem in the future.
1. Definition and Diagnosis
Some investigators have suggested that the diagnosis of DHF can be made clinically if there is reliable evidence of congestive heart failure and normal LVEF; in such circumstances, these investigators suggest, objective evidence of diastolic dysfunction obtained in a catheterisation laboratory merely confirms the diagnosis. However, most authorities make other recommendations.
presence of signs or symptoms of heart failure;
evidence of normal LV systolic function;
evidence of abnormal LV relaxation, filling or diastolic stiffness.
Vasan and Levy revised these criteria and proposed the terms ‘definite’, ‘probable’ and ‘possible’ DHF. Each of these categories requires that both signs and symptoms of heart failure be present. For the diagnosis of definite or probable DHF, an LVEF >50% must also have been documented, with the LVEF having been assessed within 72 hours of heart failure event. In addition, a definite diagnosis of DHF requires evidence of diastolic dysfunction measured by means of invasive techniques.
According to the new updated American College of Cardiology/American Heart Association guidelines, a definite diagnosis of DHF can be made when the rate of ventricular relaxation is slowed in a patient with clinical manifestations of heart failure and normal LV systolic function. This physiological abnormality is characteristically associated with an elevated LV filling pressure in a patient with normal LV volumes and contractility.
Evidence of abnormal diastolic function is essential for a definite diagnosis of DHF because a number of conditions other than DHF can result in clinical heart failure despite normal LV systolic function. These conditions include valvular heart diseases, high output failure and sleep apnoea syndrome. For the same reason, one must recognise that the term DHF and heart failure with preserved systolic function are not synonymous and one should be cautious about using them interchangeably. In practice, the diagnosis of DHF is generally based on the finding of typical symptoms and signs of heart failure in a patient who has a normal LVEF and no valvular abnormalities (e.g. aortic stenosis or mitral regurgitation) on echocardiography.
In the elderly, the diagnosis of DHF is at times difficult because certain symptoms such as fatigue and poor exercise tolerance are not uncommon in this age group and are therefore less specific for particular conditions. The sedentary lifestyle of the elderly may also mask some of the symptoms of DHF and can lead to a delay in diagnosis. Additionally, whereas noninvasive methods of treatment (especially those that rely on Doppler echocardiography) may assist in the diagnosis of heart failure with normal LVEF, these tests have significant limitations in the elderly because cardiac filling patterns are readily altered by the aging process as well as by nonspecific and transient changes in loading conditions of the heart.
E/A velocity ratio <1 : 1 or >2 : 1;
E wave deceleration time <150 m/sec or >220 m/sec;
isovolumetric relaxation time <60 m/sec or >100 m/sec;
pulmonary vein systolic and diastolic velocities ratio initially increases and then decreases as the severity of diastolic dysfunction increases;
mitral annular tissue Doppler Em velocity (i.e. myocardial velocity during early filling) at any site <8 cm/sec.
pseudonormalisation (apparently normal mitral inflow despite worsening diastolic dysfunction);
Yamaguchi et al. reported that an elevation of brain natriuretic peptide (BNP) appears to be a hallmark of patients with or at risk of DHF. BNP has also been shown to correlate with the presence and severity of diastolic dysfunction on echocardiography.[22,23] A higher cut-off level of BNP for diagnosis of heart failure has been suggested because of higher BNP values in ‘healthy elderly’. Furthermore, female sex has been found to be an independent predictor of BNP levels in the elderly. Thus, the optimal threshold of BNP for DHF in the elderly should also be sex specific.
2. Aetiology and Mechanisms of Diastolic Heart Failure (DHF)
left ventricular hypertrophy (LVH) as a result of aortic stenosis, chronic hypertension or hypertrophic cardiomyopathy;
pericardial diseases, such as constrictive pericarditis, tamponade or constrictive-effusive disease as a result of prior radiations;
restrictive cardiomyopathy, such as amyloid heart disease and idiopathic restrictive cardiomyopathy;
The vast majority of patients with DHF have a history of hypertension, and many, if not most, have some evidence of LVH on echocardiography. Most patients with DHF have a detectable structural abnormality of the heart, including LVH, atrial dilation, mitral annular calcification, aortic sclerosis or myocardial scarring.[14,25] However, some patients who present with heart failure and relatively preserved LVEF have no identifiable myocardial pathology.
Heart failure associated with relatively preserved LVEF is age-dependent, increasing from <15% in middle-aged patients to >40% in patients ≥70 years of age. Elderly patients with DHF usually have hypertension, diabetes mellitus, or both, and often coronary artery disease or atrial fibrillation. These conditions can adversely affect the diastolic properties of the heart or decrease the time available for ventricular filling. Because hypertension and the aging process produce similar changes in LV filling dynamics, diastolic dysfunction is accentuated in elderly hypertensive patients.
3. Pathophysiological Alterations Leading to DHF
Altered ventricular relaxation and abnormal ventricular filling are the hallmarks of DHF. Cardiac fibrosis and cellular disarray are the most important factors responsible for diastolic dysfunction. LVH leads to increased passive stiffness and asynchrony in myocardial fibre contraction. In addition, the abnormal loading, ischaemia, and abnormal calcium flux lead to reduced ventricular relaxation.
As a result of these alterations in myocardial relaxation and filling properties, heart chamber compliance is reduced, the time course of filling is altered and diastolic pressure is elevated. Under these circumstances, a relatively small increase in central blood volume or increase in venous tone, arterial stiffness or both can cause a substantial increase in left atrial and pulmonary venous pressures and may result in pulmonary oedema, leading to various manifestations of heart failure.[6,7,27]
The increased incidence of DHF with age may be related to the fact that aging has a greater impact on ventricular filling characteristics than on EF. Aging is associated with decreases in the elastic properties of the heart and great vessels, which leads to an increase in systolic blood pressure and an increase in myocardial stiffness. With advancing age, diffuse foci of fibrosis resulting from increased interstitial collagen accumulation in the myocardium have been reported. These deleterious effects are exacerbated by a decrease in β-adrenoceptor density and a decline in peripheral vasodilator capacity.
4. Role of Aldosterone in DHF
Serum aldosterone levels have been shown to rise with increasing age. Aldosterone levels are elevated in elderly patients with DHF compared with age-matched normal subjects, but not as high as in SHF.
As previously stated, cardiac fibrosis is a major determinant of diastolic function in the heart. Aldosterone has been repeatedly shown to play a crucial role in the development cardiac fibrosis.[31,32] In fact, in experimental animals, myocardial fibrosis occurs predominantly in the presence of elevated aldosterone despite a comparable degree of LVH. Aldosterone increases myocardial fibrosis by increasing extracellular matrix and collagen deposition via its direct effect on the mineralocorticoid receptors within the myocardium. This effect has been demonstrated to be independent of the effect of aldosterone on blood pressure or the presence of angiotension II.[32, 33, 34] In animal models, histological features of aldosterone-induced cardiac fibrosis include proliferation of myocytes and fibroblasts and intense perivascular inflammation in the heart.[35,36] Aldosterone has also been shown to increase LV mass index in hypertensive patients independently of plasma renin activity.
Additionally, aldosterone has been implicated in the pathophysiology of vascular fibrosis, resulting in less compliant vasculature.[38,39] Aldosterone has recently been shown to activate expression of human vascular muscle cell genes including those that are involved in vascular fibrosis. Decreased compliance of the systemic arterial circulation is a major factor responsible for development of systolic hypertension in the elderly. Systolic hypertension, a common condition in the elderly, is an important contributing factor to LVH and subsequent cardiac dysfunction.
5. Management of DHF
Unlike the situation with treatment of SHF, few clinical trials are available to guide the management of patients with DHF. The management of DHF has two objectives: to reverse the consequences of DHF; and to eliminate or reduce the factors responsible for diastolic dysfunction.
Initial treatment of DHF, similar to that of SHF, is aimed at reducing pulmonary congestion. Aggressive diuresis may result in serious hypotension in patients with DHF because of the steep curve of LV diastolic pressure in relation to volume. There are insufficient data from randomised trials to assess the effects of various pharmacological agents on DHF. Certain pharmacological agents have been proposed for use in patients with DHF because of their biological effects, such as elimination of tachycardia, ischaemia or both (β-adrenoceptor antagonists and rate-lowering calcium channel antagonists), or regression of LVH (diuretics and ACE inhibitors)[42,43] and fibrosis (spironolactone).
A recently reported large, randomised trial included patients with heart failure and normal LVEF, thereby demonstrating that studies in such patients can be conducted. However, in this trial, addition of candesartan cilexetil to the standard treatment regimen for patients with symptomatic heart failure and preserved LV systolic function had only a modest impact on the rate of admissions for heart failure and no significant effect on mortality or the primary endpoint.
5.1 Role of Aldosterone Antagonists in DHF
In 1998, Degre et al. reported the results of their study evaluating the effect of the combination of spironolactone (25mg)/altizide (15mg) in patients with mild to moderate hypertension. Patients were eligible for the study only if their blood pressure reduced to <160mm Hg/95mm Hg after 2 months of treatment. The total of 71 participants were then treated and followed for another 4 months. These investigators found that spironolactone/altizide significantly reduced posterior and septal wall thickness, LV end-diastolic dimension and LV mass index. Moreover, complete regression of LVH was observed in slightly more than one-third of patients.
Approximately 4 years later, two independent groups of investigators reported beneficial effects of aldosterone antagonists on diastolic function in patients with essential hypertension.[51,52] Grandi et al. reported that 6 months of treatment with canrenone significantly improved M-mode echocardiographic indices of diastolic function in 34 hypertensive patients with diastolic dysfunction. This effect was noted despite unchanged blood pressure and a similar decrease in LV mass index to that seen in control subjects. Sato et al., in the same month, reported their findings in 20 subjects with essential hypertension and LVH randomised to ACE inhibitor alone or a combination of ACE inhibitor and spironolactone 25 mg/day for 60 weeks. Despite a similar effect on blood pressure as ACE inhibitor monotherapy, the combination therapy of ACE inhibitor and spironolactone resulted in a significantly greater reduction in LV mass. The E/A ratio for mitral flow improved to the same extent in both groups but a significant reduction in procollagen type III amino-terminal peptide, a serum marker of fibrosis, was observed only in the group randomised to combination therapy. Pitt et al. studied the effect of eplerenone, enalapril and their combination for 9 months on regression of LVH in patients with hypertension. They concluded that eplerenone was as effective as enalapril in reducing LVH and blood pressure, whereas the combination was more effective than eplerenone alone. Mottram et al. also reported improved myocardial function in hypertensive patients with diastolic dysfunction after treatment with aldosterone antagonists for 6 months; this improvement was independent of changes in blood pressure.
We have recently reported our study on the effect of spironolactone on diastolic function in the elderly. In this study, 30 elderly patients (>65 years of age) with isolated diastolic dysfunction were randomised to spironolactone 25 mg/day or placebo for 4 months. The mean age of patients in the spironolactone and placebo groups, respectively, was 71 ± 5 and 72 ± 7 years. Approximately half of the subjects in both groups were taking concomitant renin-angiotensin system blockers (ACE inhibitors or angiotensin II type 1 [AT1] receptor antagonists). Spironolactone was found to significantly improve ventricular diastolic performance, as assessed by mitral Doppler inflow deceleration time and E/A ratio, despite having no significant effect on haemodynamics. In contrast to Sato et al., we were unable to demonstrate a significant difference between spironolactone and placebo in terms of serum levels of procollagen type 1 carboxy-terminal peptide, a marker of cardiac fibrosis. Possible explanations for the discrepancy between the two studies with respect to this finding are differences in the study population, length of treatment and markers used in these studies. However, the effect of spironolactone on myocardial fibrotic activity has been demonstrated in patients with advanced SHF. In the subsequent analysis of the Randomized Aldactone Evaluation Study mortality trial, a strong relationship between clinical benefits and the effects of spironolactone on serum markers of cardiac fibrosis was observed, suggesting that the beneficial effect of spironolactone arises from its effect on myocardial collagen turnover.
Additionally, spironolactone has been shown to inhibit mineralocorticoid receptor-mediated fibrotic gene expression in vascular muscle cells. Improved vascular compliance has also been reported in hypertensive patients who were taking an aldosterone antagonist.
In summary, the existing data, albeit limited, are consistent in terms of the potential benefit of aldosterone antagonists on diastolic function. The beneficial effect of spironolactone on diastolic function occurs at a dosage that has no effect on blood pressure and appears to be additive to the effects of ACE inhibitor and AT1 receptor antagonists. The available studies have also consistently demonstrated that use of aldosterone antagonists can lead to significant regression of LVH as well as an improvement of vascular elasticity in patients with essential hypertension. The mechanism responsible for the observed benefit of spironolactone in diastolic dysfunction is probably a result of its effect on myocardial fibrosis; however, further confirmatory studies are needed.
DHF is common in the elderly. The currently available treatments for this condition remain suboptimal. Aldosterone inhibition appears to be a promising therapeutic approach but only limited data evaluating this treatment option exist. Thus far, studies of aldosterone antagonists in DHF have not been adequately powered to assess their potential beneficial effects on ‘hard’ endpoints such as rate of hospitalisations or mortality. We strongly believe that large-scale studies evaluating the effect of aldosterone antagonists on major clinical outcomes in patients with diastolic dysfunction and/or DHF are warranted.
No work resembling the enclosed article has been published or is submitted for publication elsewhere. We certify that we have each made a substantial contribution so as to qualify for authorship. We did not receive any financial support for our work and do not have any potential conflicts of interest.
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