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Pharmacotherapy of heart failure with normal ejection fraction (HFNEF) - a systematic review
British Journal of Clinical Pharmacology
Abstract
The pharmacotherapy for heart failure with normal ejection fraction (HFNEF) is not as well defined as that for the treatment for heart failure with reduced ejection fraction (HFREF). Studies of the various drugs given for HFNEF have revealed conflicting results. The aim of this systematic review was to determine whether there is any benefit with pharmacotherapy in HFNEF in terms of cardiac outcomes.
Electronic and printed sources were searched until August 2010 for randomized controlled clinical trials (RCTs) comparing drug therapy with placebo in HFNEF. Weighted mean difference and pooled odds ratio (OR) with 95% confidence intervals were calculated.
A total of six RCTs including 8410 patients with a mean follow-up period of 21 months were included in the analysis. Although there were no significant differences in all cause mortality between the two groups (pooled OR 0.95, 95% CI 0.79, 1.13, P= 0.55), the subgroup analysis revealed a slight but non significant advantage with the β-adrenoceptor blocker group. There was no significant difference between the two groups in terms of cardiovascular mortality, hospitalization, worsening heart failure, ejection fraction, E : A ratio, deceleration time and E : E' ratio.
There was no significant benefit of pharmacotherapy in HFNEF. This might have been because of a lack of stringent inclusion criteria for patients in the trials and lower power of the studies. Hence trials with well defined inclusion criteria, better power, longer follow-up periods and with echocardiographic parameters as endpoints are required to shed further light on this topic.
... [5][6][7] Patients with HFNEF who received conventional treatment still have problems, such as low exercise capacity and low quality of life. [8] Previous clinical studies [9][10][11][12] suggested that traditional Chinese medicine (TCM) had certain efficacy in relieving symptoms, increasing activity capacity, improving quality of life, and other aspects in patients with HFNEF. However, the quality of these studies is poor. ...
Background:
The incidence of heart failure with normal ejection fraction (HFNEF) is increasing yearly, accounting for approximately half of all heart failure cases. Even after standardized treatment, the patient's prognosis is not good. Therefore, it is necessary to explore new treatment methods for HFNEF. Yangyin Shuxin Decoction, a traditional Chinese medicine prescription from our clinical experience in the treatment of HFNEF, has a potential cardioprotective effect. Preliminary clinical trials have shown that this prescription can improve the quality of life of HFNEF. This prompted us to use more objective indicators to further evaluate whether Yangyin Shuxin Decoction can improve the exercise capacity in HENEF patients.
Methods:
This is a single-center parallel randomized controlled trial. The 64 patients who met the inclusion criteria were from the Cardiovascular Clinic. They will be randomly assigned to the treatment group (Yangying Shuxin Decoction combined with standard treatment) or the control group (standard treatment) according to the ratio of 1:1. The course of treatment will be 2 weeks. Both groups were interviewed at the following time points: of at enrollment (V1), and week 2 (V2), week 4 (V3), week 8 (V4), and week 12 (V5) after enrollment. The primary indicator is the peak oxygen consumption (Peak VO2) of the cardiopulmonary exercise test (CPET). Secondary indicators include CPET indicators such as anaerobic threshold oxygen consumption, carbon dioxide ventilation equivalent slope, echocardiographic indicators such as the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity(E/e'), left atrial volume index (LAVI), left ventricular mass index (LVMI), the peak velocity of tricuspid regurgitation (TR), B-type natriuretic peptide (BNP), New York Heart Association (NYHA) cardiac function grading, and so on. These indicators will be used to evaluate the effect of Yangyin Shuxin Decoction on exercise capacity in patients with HFNEF.
Discussion:
At present, it is unclear whether the exercise capacity can be maintained after long-term use of Yangyin Shuxin Decoction. In this study, we will evaluate whether Yangyin Shuxin Decoction can improve the exercise capacity and quality of life of patients with HFNEF. This will provide an objective basis for the therapeutic effect of traditional Chinese medicine on HFNEF.
Trial registration:
This study protocol has been listed in the Chinese Clinical Trial Registry (registration number: ChiCTR-IOR-17014206, http://www.chictr.org.cn/showproj.aspx?proj=24304) on December 28, 2017.
... A number of cohort studies and meta-analyses reported a nonsignificant influence on mortality and rehospitalization risks with beta blockers in HFpEF. [15][16][17][18] Few researchers reported a beneficial effect of carvedilol, a combined alpha and beta blocker in diastolic HF with preserved systolic function. [19][20][21] Japanese diastolic HF study (J-DHF), however, failed to show a significant advantage of carvedilol over placebo on composite end point of cardiovascular death and hospitalization. ...
Background
There is a lack of evidence-based therapies for the treatment of heart failure (HF) with preserved ejection fraction (HFpEF). Beta blockers may provide some benefit in HFpEF due to their proven role in HF with reduced ejection fraction.
Aim
The main objective of the present study was to evaluate the efficacy of controlled-release metoprolol (metoprolol succinate) in HFpEF.
Materials and Methods
This was an investigator-initiated, randomized, double-blind, placebo-controlled, 14-week pilot study with metoprolol succinate as a study drug. Dose titration protocol was used with optional upward titration of doses ranging from 25 to 100 mg. The end points included clinical, echocardiographic, biochemical (N-terminal pro-B-type natriuretic peptide and serum carboxy-terminal propeptide of procollagen type I), and quality of life (QoL) (SF-36) parameters.
Results
Twenty patients were enrolled in each of the treatment arms. An improvement in New York Heart Association class and exercise capacity was seen in both treatment arms. The mean change in various echocardiographic and biochemical parameters between the two groups was statistically insignificant. A significant improvement in some QoL parameters was observed in both the groups. No serious adverse events were seen.
Conclusion
Hence, this pilot study showed that metoprolol succinate possibly has some beneficial role in HFpEF as reflected by improvement in some parameters. The findings highlight the need of a larger study with longer follow-up to provide a definitive answer.
... However, they have no significant effect on mortality during more prolonged follow-up. 67 Contrariwise, another meta-analysis found no significant difference between pharmacotherapy (including ARBS and ACEIs) and placebo in terms of CV mortality, hospitalization, and worsening HF. 68 This was also the conclusion of another pooled analysis of the 3 major randomized trials of RAS inhibition in HFPEF (CHARM-Preserved, I-PRESERVE, and Perindopril in Elderly People with Chronic HF). 69 Nevertheless, more recently a prospective study from the Swedish HF Registry found that among patients with HF and preserved ejection fraction, the use of RAS antagonists was associated with lower all-cause mortality. ...
The two major classes of drugs that target the RAS are the angiotensin-converting enzyme (ACE) inhibitors and the selective AT1 receptor blockers (ARBs). Although both of these drug classes target angiotensin II, the differences in their mechanisms of action have implications for their effects on other pathways and receptors that may have therapeutic implications. Both ACEIs and ARBs are effective antihypertensive agents that have been shown to reduce the risk of cardiovascular and renal events. Direct inhibition of renin -the most proximal aspect of the RAS -became clinically feasible from 2007 with the introduction of aliskiren. This latter drug has been shown to be efficacious for the management of hypertension. Combined therapy of direct renin-inhibitors with ACEIs or ARBs has been tested in some clinical situations as congestive HF and proteinuria with diverse results. This article tries to offer an updated review of current knowledge on the use of RAS blocking drugs in clinical settings.
A insuficiência cardíaca (IC) é uma síndrome prevalente que, apesar dos avanços no tratamento, acarreta significativa morbidade e mortalidade. Estudos demonstram que a não adesão ao tratamento é uma importante causa de resultados insatisfatórios na terapia, descompensação no quadro clínico, internação e óbito. Acreditando-se que a efetiva inserção do farmacêutico na assistência, mesmo na dispensação convencional, seria capaz de promover maior adesão, tevese por objetivo avaliar como dois modelos de atuação farmacêutica impactam sobre a adesão à farmacoterapia em pacientes com IC com fração de ejeção reduzida assistidos em dois centros clínicos especializados da rede pública de saúde. O trabalho foi organizado em duas partes. A primeira parte foi um estudo prospectivo com análise transversal de dados de pacientes com ICFER acompanhadas por uma equipe multidisciplinar, no momento da inserção do profissional farmacêutico nessa equipe e após 4 meses, com orientação farmacêutica por demanda do paciente. A segunda parte é a análise transversal de um estudo prospectivo que realizou acompanhamento farmacoterapêutico com pacientes de outro centro clínico especializado, por 4 meses. Foram incluídos respectivamente 38 e 31 pacientes. Nos dois grupos, observou-se maioria de homens, com predomínio de IC leve a moderada, polimedicados e tratando duas ou mais comorbidades, utilizando combinação de betabloqueador, inibidores da enzima conversora da angiotensina e/ou antagonistas dos receptores da angiotensina, antagonista da aldosterona e diurético. Na primeira parte do estudo, observou-se associação de maior número de comorbidades, maior gravidade e polifarmácia com boa adesão. Na segunda parte, verificou-se associação de idade maior, viver sem cônjuge e com menor número de pessoas no mesmo lar, razão de posse de medicamentos e razão para não tomar o medicamento com a adesão. Os resultados sobre adesão melhoraram nos dois grupos, ao final do estudo, embora sem significância estatística. Na segunda parte observou-se melhora estatisticamente significante no nível de conhecimento da prescrição, na razão de posse de medicamentos e na autoavaliação de saúde. Não foi possível observar melhora significativa na adesão, porém verificaram-se melhorias significativas em fatores associados à boa adesão. O limitado número amostral exigirá cautela na extrapolação dos resultados.
Drugs used for the treatment of heart failure and for management of arrhythmias are discussed. Their major mechanisms of action, key pharmacokinetic principles essential for their safe use, and important side effects are explained. Each class of drug is also given context for effective clinical use.
Approximately 5 million people in the United States have heart failure (HF), with an additional 500,000 getting diagnosed with HF each year. 1 Nearly a million people were hospitalized with HF as the primary diagnosis in 1999, with up to twice the number being hospitalized with HF as a secondary diagnosis. 2 Despite recent declines, the HF hospitalization rate remains >2000/100,000 person-years among Medicare beneficiaries as of 2008, with a 1-year mortality of 29.6%. 3 Many of these patients will present to the operating room, presenting challenges to the anesthesiologists, as HF is one of the major clinical predictors of perioperative adverse cardiac events.4 This article reviews nonsurgical therapy for HF and specifically addresses medication therapy, cardiac resynchronization, and the use of implantable cardioverter-defibrillator (ICD) in HF patients.
Limited information exists regarding the role of left ventricular function in predicting exercise capacity and impact on age- and sex-related differences.
To determine the impact of measures of cardiac function assessed by echocardiography on exercise capacity and to determine if these associations are modified by sex or advancing age.
Cross-sectional study of patients undergoing exercise echocardiography with routine measurements of left ventricular systolic and diastolic function by 2-dimensional and Doppler techniques. Analyses were conducted to determine the strongest correlates of exercise capacity and the age and sex interactions of these variables with exercise capacity.
Large tertiary referral center in Rochester, Minnesota, in 2006.
Patients undergoing exercise echocardiography using the Bruce protocol (N = 2867). Patients with echocardiographic evidence of exercise-induced ischemia, ejection fractions lower than 50%, or significant valvular heart disease were excluded.
Exercise capacity in metabolic equivalents (METs).
Diastolic dysfunction was strongly and inversely associated with exercise capacity. Compared with normal function, after multivariate adjustment, those with moderate/severe resting diastolic dysfunction (-1.30 METs; 95% confidence interval [CI], -1.52 to -0.99; P < .001) and mild resting diastolic dysfunction (-0.70 METs; 95% CI, -0.88 to -0.46; P < .001) had substantially lower exercise capacity. Variation of left ventricular systolic function within the normal range was not associated with exercise capacity. Left ventricular filling pressures measured by resting E/e' of 15 or greater (-0.41 METs; 95% CI, -0.70 to -0.11; P = .007) or postexercise E/e' of 15 or greater (-0.41 METs; 95% CI, -0.71 to -0.11; P = .007) were similarly associated with a reduction in exercise capacity, each in separate multivariate analyses. Individuals with impaired relaxation (mild dysfunction) or resting E/e' of 15 or greater had a progressive increase in the magnitude of reduction in exercise capacity with advancing age (P < .001 and P = .02, respectively). Other independent correlates of exercise capacity were age (unstandardized beta coefficient, -0.85 METs; 95% CI, -0.92 to -0.77, per 10-year increment; P < .001), female sex (-1.98 METs; 95% CI, -2.15 to -1.84; P < .001), and body mass index greater than 30 (-1.24 METs; 95% CI, -1.41 to -1.10; P < .001).
In this large cross-sectional study of those referred for exercise echocardiography and not limited by ischemia, abnormalities of left ventricular diastolic function were independently associated with exercise capacity.
Approximately 50% of patients with heart failure have a left ventricular ejection fraction of at least 45%, but no therapies have been shown to improve the outcome of these patients. Therefore, we studied the effects of irbesartan in patients with this syndrome.
We enrolled 4128 patients who were at least 60 years of age and had New York Heart Association class II, III, or IV heart failure and an ejection fraction of at least 45% and randomly assigned them to receive 300 mg of irbesartan or placebo per day. The primary composite outcome was death from any cause or hospitalization for a cardiovascular cause (heart failure, myocardial infarction, unstable angina, arrhythmia, or stroke). Secondary outcomes included death from heart failure or hospitalization for heart failure, death from any cause and from cardiovascular causes, and quality of life.
During a mean follow-up of 49.5 months, the primary outcome occurred in 742 patients in the irbesartan group and 763 in the placebo group. Primary event rates in the irbesartan and placebo groups were 100.4 and 105.4 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% confidence interval [CI], 0.86 to 1.05; P=0.35). Overall rates of death were 52.6 and 52.3 per 1000 patient-years, respectively (hazard ratio, 1.00; 95% CI, 0.88 to 1.14; P=0.98). Rates of hospitalization for cardiovascular causes that contributed to the primary outcome were 70.6 and 74.3 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% CI, 0.85 to 1.08; P=0.44). There were no significant differences in the other prespecified outcomes.
Irbesartan did not improve the outcomes of patients with heart failure and a preserved left ventricular ejection fraction. (ClinicalTrials.gov number, NCT00095238.)
The potent mineralocorticoid aldosterone has a multifaceted role in the pathogenesis of congestive heart failure. In addition to its contribution to salt and water retention, it also promotes organ fibrosis. Although angiotensin-converting–enzyme inhibitors have important therapeutic benefit in heart failure, they do not eliminate the effects of aldosterone. Thus, recent studies have underscored the value of aldosterone-receptor antagonists, such as spironolactone, in the treatment of chronic heart failure. This review article gives an in-depth update on the mechanisms of action of aldosterone and their implications for therapy.
The importance of heart failure with preserved ejection fraction is increasingly recognized. We conducted a study to evaluate the epidemiologic features and outcomes of patients with heart failure with preserved ejection fraction and to compare the findings with those from patients who had heart failure with reduced ejection fraction.
From April 1, 1999, through March 31, 2001, we studied 2802 patients admitted to 103 hospitals in the province of Ontario, Canada, with a discharge diagnosis of heart failure whose ejection fraction had also been assessed. The patients were categorized in three groups: those with an ejection fraction of less than 40 percent (heart failure with reduced ejection fraction), those with an ejection fraction of 40 to 50 percent (heart failure with borderline ejection fraction), and those with an ejection fraction of more than 50 percent (heart failure with preserved ejection fraction). Two groups were studied in detail: those with an ejection fraction of less than 40 percent and those with an ejection fraction of more than 50 percent. The main outcome measures were death within one year and readmission to the hospital for heart failure.
Thirty-one percent of the patients had an ejection fraction of more than 50 percent. Patients with heart failure with preserved ejection fraction were more likely to be older and female and to have a history of hypertension and atrial fibrillation. The presenting history and clinical examination findings were similar for the two groups. The unadjusted mortality rates for patients with an ejection fraction of more than 50 percent were not significantly different from those for patients with an ejection fraction of less than 40 percent at 30 days (5 percent vs. 7 percent, P=0.08) and at 1 year (22 percent vs. 26 percent, P=0.07); the adjusted one-year mortality rates were also not significantly different in the two groups (hazard ratio, 1.13; 95 percent confidence interval, 0.94 to 1.36; P=0.18). The rates of readmission for heart failure and of in-hospital complications did not differ between the two groups.
Among patients presenting with new-onset heart failure, a substantial proportion had an ejection fraction of more than 50 percent. The survival of patients with heart failure with preserved ejection fraction was similar to that of patients with reduced ejection fraction.
Unlike heart failure with a low ejection fraction, there is no evidence-based treatment for heart failure with preserved ejection fraction which improves clinical outcomes. Indeed, the only evidence for any treatment effect comes from small studies with verapamil where this drug increased exercise capacity and reduced a heart failure score. Large trials are presently underway which are examining the effect of treatment with an ACE inhibitor, ARB and aldosterone antagonist in patients with heart failure and preserved ejection fraction.
Aims: To evaluate the effect of considerably high left ventricular filling pressure with mitral regurgitation on mitral annular velocity during early diastole.
Subjects: Two hundred and forty-three patients who underwent cardiac catheterization for evaluation of chest pain.
Methods: Mitral annular velocity during early diastole was measured by colour M-mode tissue Doppler imaging. Patients were divided into the following three groups according to the cardiac catheterization data. Group A (n=147): patients having left ventricular relaxation time constant τ<46 ms and left ventricular end-systolic volume index <38 ml m−2; group B (n=88): patients having τ≥46 ms and/or end-systolic volume index ≥38 ml m−2; group C (n=8): patients having mean pulmonary capillary wedge pressure ≥16 mmHg in addition to τ≥46 ms and end-systolic volume index ≥38 ml m−2.
Results: Mitral annular velocity during early diastole was significantly less in group B (4·8±1·4 cm s−1) than in group A (7·7±1·9 cm s−1). However, there was no significant difference between groups A and C (8·3±0·8 cm s−1). A transmitral E/A >1·0 was observed in 12/147 patients of group A, 10/88 of group B, and 8/8 of group C. The incidence of ≥Sellers' grade II mitral regurgitation was higher in group C than the others.
Conclusions: A paradoxically faster mitral annular velocity during early diastole is found in patients having left ventricular dysfunction with moderate to severe mitral regurgitation and considerably high left ventricular filling pressure. Attention should be paid to an interpretation of mitral annular velocity during early diastole regarding left ventricular early diastolic performance in patients having mitral regurgitation with an E/A >1·0 in their transmitral flow. Copyright 2002 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.
Summary Background Angiotensin-converting-enzyme (ACE) inhibitors improve outcome of patients with chronic heart failure (CHF). A substantial proportion of patients, however, experience no benefit from ACE inhibitors because of previous intolerance. We aimed to find out whether candesartan, an angiotensinreceptor blocker, could improve outcome in such patients not taking an ACE inhibitor. Methods Between March, 1999, and March, 2001, we enrolled 2028 patients with symptomatic heart failure and left-ventricular ejection fraction 40% or less who were not receiving ACE inhibitors because of previous intolerance. Patients were randomly assigned candesartan (target dose 32 mg once daily) or matching placebo. The primary outcome of the study was the composite of cardiovascular death or hospital admission for CHF. Analysis was by intention to treat. Findings The most common manifestation of ACE-inhibitor intolerance was cough (72%), followed by symptomatic hypotension (13%) and renal dysfunction (12%). During a median follow-up of 33·7 months, 334 (33%) of 1013 patients in the candesartan group and 406 (40%) of 1015 in the placebo group had cardiovascular death or hospital admission for CHF (unadjusted hazard ratio 0·77 [95% CI 0·67–0·89], p=0·0004; covariate adjusted 0·70 [0·60–0·81], p<0·0001). Each component of the primary outcome was reduced, as was the total number of hospital admissions for CHF. Study-drug discontinuation rates were similar in the candesartan (30%) and placebo (29%) groups. Interpretation Candesartan was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic chronic heart failure and intolerance to ACE inhibitors.
Context:
Approximately half of patients with overt congestive heart failure (CHF) have diastolic dysfunction without reduced ejection fraction (EF). Yet, the prevalence of diastolic dysfunction and its relation to systolic dysfunction and CHF in the community remain undefined.
Objectives:
To determine the prevalence of CHF and preclinical diastolic dysfunction and systolic dysfunction in the community and determine if diastolic dysfunction is predictive of all-cause mortality.
Design, setting, participants:
Cross-sectional survey of 2042 randomly selected residents of Olmsted County, Minnesota, aged 45 years or older from June 1997 through September 2000.
Main outcome measures:
Doppler echocardiographic assessment of systolic and diastolic function. Presence of CHF diagnosis by review of medical records with designation as validated CHF if Framingham criteria are satisfied. Subjects without a CHF diagnosis but with diastolic or systolic dysfunction were considered as having either preclinical diastolic or preclinical systolic dysfunction.
Results:
The prevalence of validated CHF was 2.2% (95% confidence interval [CI], 1.6%-2.8%) with 44% having an EF higher than 50%. Overall, 20.8% (95% CI, 19.0%-22.7%) of the population had mild diastolic dysfunction, 6.6% (95% CI, 5.5%-7.8%) had moderate diastolic dysfunction, and 0.7% (95% CI, 0.3%-1.1%) had severe diastolic dysfunction with 5.6% (95% CI, 4.5%-6.7%) of the population having moderate or severe diastolic dysfunction with normal EF. The prevalence of any systolic dysfunction (EF < or =50%) was 6.0% (95% CI, 5.0%-7.1%) with moderate or severe systolic dysfunction (EF < or =40%) being present in 2.0% (95% CI, 1.4%-2.5%). CHF was much more common among those with systolic or diastolic dysfunction than in those with normal ventricular function. However, even among those with moderate or severe diastolic or systolic dysfunction, less than half had recognized CHF. In multivariate analysis, controlling for age, sex, and EF, mild diastolic dysfunction (hazard ratio, 8.31 [95% CI, 3.00-23.1], P<.001) and moderate or severe diastolic dysfunction (hazard ratio, 10.17 [95% CI, 3.28-31.0], P<.001) were predictive of all-cause mortality.
Conclusions:
In the community, systolic dysfunction is frequently present in individuals without recognized CHF. Furthermore, diastolic dysfunction as rigorously defined by comprehensive Doppler techniques is common, often not accompanied by recognized CHF, and associated with marked increases in all-cause mortality.
Despite use of similar drugs, outcomes of recent heart failure (HF) trials were frequently neutral in heart failure with normal left ventricular ejection fraction (HFNEF) and positive in heart failure with reduced left ventricular ejection fraction (HFREF). The neutral outcomes of HFNEF trials were often attributed to deficient HFNEF patient recruitment with inclusion of many HFREF or noncardiac patients. Patient recruitment criteria of 21 HFNEF trials were therefore reviewed in reference to diagnostic guidelines for HFNEF. In the 4 published sets of guidelines, a definite diagnosis of HFNEF required the simultaneous and obligatory presence of signs and/or symptoms of HF and evidence of normal systolic left ventricular (LV) function and of diastolic LV dysfunction. In 3 of 4 sets of guidelines, normal systolic LV function comprised both a left ventricular ejection fraction (LVEF) >50% and an absence of LV dilation. Among the 21 HFNEF trials, LVEF cutoff values ranged from 35% to 50%, with only 8 trials adhering to an LVEF >50%. Furthermore, only 1 trial specified a normal LV end-diastolic dimension as an enrollment criterion and only 7 trials required evidence of diastolic LV dysfunction. Nonadherence to diagnostic guidelines induced excessive enrollment into HFNEF trials of HF patients with eccentric LV remodeling and ischemic heart disease compared with HF patients with concentric LV remodeling and arterial hypertension. Nonadherence to guidelines also led to underpowered HFNEF trials with a low incidence of outcome events such as death or HF hospitalizations. Future HFNEF trials should therefore adhere to diagnostic guidelines for HFNEF.
Left atrial (LA) enlargement is related to left ventricular (LV) remodelling and diastolic dysfunction (DD), reflecting cardiac target organ damage. The aim of this study was to investigate the relation of one-dimensional (1D) and volume derived indexes of LA enlargement with abnormal segmental relaxation in hypertensive patients.
We evaluated 90 hypertensive patients and 50 non-hypertensive volunteers with normal ejection fraction (EF). Global DD was evaluated based on conventional indexes (E/A, deceleration time, LV isovolumic relaxation time), and segmental early and late diastolic strain rates (SR) were recorded from 18 LV segments. The number of segments with abnormal relaxation (SR(E)/SR(A) < 1.1) was represented as segmental DD. LA size was evaluated based on 1D left atrial dimension (LAD) and left atrial volume (LAV), and indexed by body surface area (BSA) and height. The hypertensive patients had higher segmental DD (9.5 +/- 4.2 vs. 5.2 +/- 3.2, P < 0.05) and appeared to have higher 1D and volume-derived indexes of LA size compared to the controls. Individuals with global DD had more deteriorated segmental relaxation and higher LA size compared with those without global DD. When participants were separated according to normal, mildly dilated, and moderately to severely dilated LA size, there was progressive deterioration of segmental DD, mean Ea, and filling pressures, along with the progression of LA enlargement. Volume-derived indexes, LAV/BSA, LAV/height, and LAV, appeared to have better correlations with segmental DD, as well as with linearly changed parameters of DD (Mean Ea, E/Ea), LV remodelling (LVMI, relative wall thickness), age, and systolic blood pressure (SBP), compared to the respective 1D-based (LAD) LA indexes. LAV/BSA was proved to be an independent predictor of segmental DD (beta: 0.23, R(2): 0.48), along with LVMI, SBP and age, irrespective of gender.
LA size constitutes a morphological expression of abnormal segmental relaxation, with volume-derived indexes of LA enlargement, exhibiting higher correlation with segmental DD compared to the respective 1D indexes, and LAV/BSA to be an independent predictor of segmental DD in hypertensive heart disease.
In this pre-specified subanalysis of the SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure) trial, which examined the effects of nebivolol in elderly heart failure (HF) patients, we explored the effects of left ventricular ejection fraction (EF) on outcomes, including the subgroups impaired EF (< or =35%) and preserved EF (>35%).
Beta-blockers are established drugs in patients with HF and impaired EF, but their value in preserved EF is unclear.
We studied 2,111 patients; 1,359 (64%) had impaired (< or =35%) EF (mean 28.7%) and 752 (36%) had preserved (>35%) EF (mean 49.2%). The effect of nebivolol was investigated in these 2 groups, and it was compared to explore the interaction of EF with outcome. Follow-up was 21 months; the primary end point was all-cause mortality or cardiovascular hospitalizations.
Patients with preserved EF were more often women (49.9% vs. 29.8%) and had less advanced HF, more hypertension, and fewer prior myocardial infarctions (all p < 0.001). During follow-up, the primary end point occurred in 465 patients (34.2%) with impaired EF and in 235 patients (31.2%) with preserved EF. The effect of nebivolol on the primary end point (hazard ratio [HR] of nebivolol vs. placebo) was 0.86 (95% confidence interval: 0.72 to 1.04) in patients with impaired EF and 0.81 (95% confidence interval: 0.63 to 1.04) in preserved EF (p = 0.720 for subgroup interaction). Effects on all secondary end points were similar between groups (HR for all-cause mortality 0.84 and 0.91, respectively), and no p value for interaction was <0.48.
The effect of beta-blockade with nebivolol in elderly patients with HF in this study was similar in those with preserved and impaired EF.
Heart failure with a normal ejection fraction (HFNEF) is a common clinical problem with many unsolved questions regarding pathophysiology, diagnosis, and therapy. Although the term diastolic heart failure has been abandoned, diastolic left ventricular (LV) dysfunction together with combined systolic ventricular and arterial stiffening are considered to be the main pathophysiologic mechanisms in HFNEF. Current guidelines define HFNEF by symptoms or signs of heart failure in the presence of LV ejection fraction of more than 50%, but with additional evidence of LV diastolic dysfunction. Definite diagnosis of HFNEF requires exclusion of valvular heart disease, constrictive pericarditis, and several noncardiac diseases. Echocardiographic assessment of the tissue Doppler-derived filling index E/E', which is the ratio of the peak early mitral valve flow velocity to the peak early diastolic mitral annular velocity, should improve the noninvasive estimation of filling pressures in suspected HFNEF. Elevated plasma levels of natriuretic peptides may confirm HFNEF if tissue Doppler echocardiography is inconclusive. Treatment of HFNEF is symptom oriented and mainly based on pathophysiologic assumptions such as heart rate reduction, blood pressure control, and maintenance of sinus rhythm. In contrast to heart failure with reduced ejection fraction, large-scale randomized controlled drug trials for HFNEF are scarce and could not demonstrate mortality reduction so far.
Diabetes mellitus (DM) is highly prevalent and is an important risk factor for congestive heart failure (HF). Increased left ventricular (LV) diastolic stiffness is recognized as the earliest manifestation of DM-induced LV dysfunction, but its pathophysiology remains incompletely understood. Mechanisms whereby DM increases LV diastolic stiffness differ between HF with normal LV ejection fraction (EF) (HFNEF) and HF with reduced LVEF (HFREF). In diabetic HFREF, fibrosis and deposition of advanced glycation end products (AGEs) are the most important contributors to high LV diastolic stiffness, whereas in diabetic HFNEF, elevated resting tension of hypertrophied cardiomyocytes is the most important contributor to high LV diastolic stiffness. As HF mortality remains high in DM despite proven efficacy of current treatments, better understanding of the pathophysiology of high LV diastolic stiffness could be beneficial for novel therapeutic strategies.
Invasive cardiopulmonary exercise testing was performed in 7 patients who presented with congestive heart failure, normal left ventricular ejection fraction and no significant coronary or valvular heart disease and in 10 age-matched normal subjects. Compared with the normal subjects, patients demonstrates severe exercise intolerance with a 48% reduction in peak oxygen consumption (11.6 +/- 4.0 versus 22.7 +/- 6.1 ml/kg per min; p less than 0.001), primarily due to a 41% reduction in peak cardiac index (4.2 +/- 1.4 versus 7.1 +/- 1.1 liters/min per m2; p less than 0.001). In patients compared with normal subjects, peak left ventricular stroke volume index (34 +/- 9 versus 46 +/- 7 ml/min per m2; p less than 0.01) and end-diastolic volume index (56 +/- 14 versus 68 +/- 12 ml/min per m2; p less than 0.08) were reduced, whereas peak ejection fraction and end-systolic volume index were not different. In patients, the change in end-diastolic volume index during exercise correlated strongly with the change in stroke volume index (r = 0.97; p less than 0.0001) and cardiac index (r = 0.80; p less than 0.03). Pulmonary wedge pressure was markedly increased at peak exercise in patients compared with normal subjects (25.7 +/- 9.1 versus 7.1 +/- 4.4 mm Hg; p less than 0.0001). Patients demonstrated a shift of the left ventricular end-diastolic pressure-volume relation upward and to the left at rest. Increases in left ventricular filling pressure during exercise were not accompanied by increases in end-diastolic volume, indicating a limitation to left ventricular filling.(ABSTRACT TRUNCATED AT 250 WORDS)
Normal left ventricular systolic performance with impaired left ventricular diastolic filling may be present in a substantial number of patients with congestive heart failure (CHF). To evaluate the effect of oral verapamil in this subset, 20 men (mean age 68 +/- 5 years) with CHF, intact left ventricular function (ejection fraction greater than 45%) and abnormal diastolic filling (peak filling rate less than 2.5 end-diastolic volumes per second [edv/s]) were studied in a placebo-controlled, double-blind 5-week crossover trial. All patients underwent echocardiography to rule out significant valvular disease, and thallium-201 stress scintigraphy to exclude major active ischemia. Compared to baseline values, verapamil significantly improved exercise capacity by 33% (13.9 +/- 4.3 vs 10.7 +/- 3.4 minutes at baseline) and peak filling rate by 30% (2.29 +/- 0.54 vs 1.85 +/- 0.45 edv/s at baseline) (all p less than 0.05). Placebo values were 12.3 +/- 4.0 minutes and 2.16 +/- 0.48 edv/s, respectively (difference not significant for both). Improvement from baseline in an objective clinico-radiographic heart failure score (scale 0 to 13) was significantly greater with verapamil compared to placebo (median improvement in score: 3 vs 1, p less than 0.01). Mean ejection fraction and systolic blood pressure were unchanged from baseline; diastolic blood pressure and heart rate decreased to a small degree. Verapamil may have therapeutic efficacy in patients with CHF, preserved systolic function and impaired diastolic filling.
Heart failure is a common and serious condition in many parts of the world and is a frequent cause for hospital admission in the Chinese population of Hong Kong. There is no published information on the epidemiology of heart failure in this community or from mainland China. Therefore, a prospective study of consecutive patients admitted with the clinical diagnosis of heart failure has been carried out to identify the main risk factors or possible causes, and other clinical data. Seven-hundred thirty consecutive patients with cardiac failure were identified and studied. Standard clinical criteria were used for diagnosis and identification of the main or most likely aetiologies and echocardiography was done in 30%. The data analysis of the 730 patients showed the following. The majority were females (56%) and the prevalence of heart failure increased with age (mean age 73.5 +/- 11.7 years) with 76% of the women > 70 years old. In contrast, the men were younger with 40% < 70 years old. The main identifiable risk factors were hypertension (37%), ischemic heart disease (31%), valvular heart disease (15%), cor pulmonale (27%), idiopathic dilated cardiomyopathy (4%), and miscellaneous (10%). In women, hypertension was the commonest cause at all ages but in men aged < 70 years ischemic heart disease was equal in frequency to hypertension (36% and 35%, respectively). Twenty-one percent had diabetes compared to a community rate of 10% for this age group (odds ratio 2.25, P < 0.0001). There was considerable overlap between diabetes, hypertension and ischemic heart disease. The estimated incidence rate was 3.8/1000 women and 3.0/1000 men aged > 45 years old.(ABSTRACT TRUNCATED AT 250 WORDS)
At 32-month follow-up of older patients with prior myocardial infarction, congestive heart failure, and a left ventricular ejection fraction > or = 40% treated with diuretics plus angiotensin-converting enzyme inhibitors, and also with digoxin if atrial fibrillation was present, propranolol caused a 35% significant reduction in total mortality and a 37% significant decrease in total mortality plus nonfatal myocardial infarction compared with no propranolol. At 1-year follow-up, propranolol caused a significantly greater increase in left ventricular ejection fraction (6%) and a significantly greater reduction in left ventricular mass (34 g) than did no propranolol (2% and 20 g, respectively).
Data are limited regarding the classification and prognosis of patients with congestive heart failure (CHF) in the community.
Using the resources of the Rochester Epidemiology Project, we evaluated all patients receiving a first diagnosis of CHF in Olmsted County, Minnesota, in 1991 (n=216). Among these patients, 88% were >/=65 years and 49% were >/=80 years of age. The prognosis of patients with a new diagnosis of CHF was poor; survival was 86+/-2% at 3 months, 76+/-3% at 1 year, and 35+/-3% at 5 years. Of the 216 patients, 137 (63%) had an assessment of ejection fraction. In these patients, systolic function was preserved (ejection fraction >/=50%) in 59 (43%) and reduced (ejection fraction <50%) in 78 (57%). Survival adjusted for age, sex, NYHA class, and coronary artery disease was not significantly different between patients with preserved and those with reduced systolic function (relative risk, 0.80; P=0.369). ACE inhibitors were used in only 44% of the total population with CHF.
The present study reports the clinical characteristics and natural history of CHF as it presents in the community in the vasodilator era. CHF is a disease of the "very elderly," frequently occurs in the setting of normal ejection fraction, and has a poor prognosis, regardless of the level of systolic function. Diagnostic and therapeutic methods are underused in the community.
The effect of volume reduction on various diastolic Doppler parameters of left ventricular filling was assessed in 13 patients before and after hemodialysis. Volume reduction decreased early diastolic mitral annular velocities to a lesser extent than early diastolic mitral inflow velocities.
To evaluate the effect of considerably high left ventricular filling pressure with mitral regurgitation on mitral annular velocity during early diastole.
Two hundred and forty-three patients who underwent cardiac catheterization for evaluation of chest pain.
Mitral annular velocity during early diastole was measured by colour M-mode tissue Doppler imaging. Patients were divided into the following three groups according to the cardiac catheterization data. Group A (n=147): patients having left ventricular relaxation time constant tau<46 ms and left ventricular end-systolic volume index <38 ml m(-2); group B (n=88): patients having tau>or=46 ms and/or end-systolic volume index >or=38 ml m(-2); group C (n=8): patients having mean pulmonary capillary wedge pressure >or=16 mmHg in addition to tau>or=46 ms and end-systolic volume index >or=38 ml m(-2).
Mitral annular velocity during early diastole was significantly less in group B (4.8+/-1.4 cm s(-1)) than in group A (7.7+/-1.9 cm s(-1)). However, there was no significant difference between groups A and C (8.3+/-0.8 cm s(-1)). A transmitral E/A >1.0 was observed in 12/147 patients of group A, 10/88 of group B, and 8/8 of group C. The incidence of >or=Sellers' grade II mitral regurgitation was higher in group C than the others.
A paradoxically faster mitral annular velocity during early diastole is found in patients having left ventricular dysfunction with moderate to severe mitral regurgitation and considerably high left ventricular filling pressure. Attention should be paid to an interpretation of mitral annular velocity during early diastole regarding left ventricular early diastolic performance in patients having mitral regurgitation with an E/A >1.0 in their transmitral flow.
Approximately half of patients with overt congestive heart failure (CHF) have diastolic dysfunction without reduced ejection fraction (EF). Yet, the prevalence of diastolic dysfunction and its relation to systolic dysfunction and CHF in the community remain undefined.
To determine the prevalence of CHF and preclinical diastolic dysfunction and systolic dysfunction in the community and determine if diastolic dysfunction is predictive of all-cause mortality.
Cross-sectional survey of 2042 randomly selected residents of Olmsted County, Minnesota, aged 45 years or older from June 1997 through September 2000.
Doppler echocardiographic assessment of systolic and diastolic function. Presence of CHF diagnosis by review of medical records with designation as validated CHF if Framingham criteria are satisfied. Subjects without a CHF diagnosis but with diastolic or systolic dysfunction were considered as having either preclinical diastolic or preclinical systolic dysfunction.
The prevalence of validated CHF was 2.2% (95% confidence interval [CI], 1.6%-2.8%) with 44% having an EF higher than 50%. Overall, 20.8% (95% CI, 19.0%-22.7%) of the population had mild diastolic dysfunction, 6.6% (95% CI, 5.5%-7.8%) had moderate diastolic dysfunction, and 0.7% (95% CI, 0.3%-1.1%) had severe diastolic dysfunction with 5.6% (95% CI, 4.5%-6.7%) of the population having moderate or severe diastolic dysfunction with normal EF. The prevalence of any systolic dysfunction (EF < or =50%) was 6.0% (95% CI, 5.0%-7.1%) with moderate or severe systolic dysfunction (EF < or =40%) being present in 2.0% (95% CI, 1.4%-2.5%). CHF was much more common among those with systolic or diastolic dysfunction than in those with normal ventricular function. However, even among those with moderate or severe diastolic or systolic dysfunction, less than half had recognized CHF. In multivariate analysis, controlling for age, sex, and EF, mild diastolic dysfunction (hazard ratio, 8.31 [95% CI, 3.00-23.1], P<.001) and moderate or severe diastolic dysfunction (hazard ratio, 10.17 [95% CI, 3.28-31.0], P<.001) were predictive of all-cause mortality.
In the community, systolic dysfunction is frequently present in individuals without recognized CHF. Furthermore, diastolic dysfunction as rigorously defined by comprehensive Doppler techniques is common, often not accompanied by recognized CHF, and associated with marked increases in all-cause mortality.
Half of patients with chronic heart failure (CHF) have preserved left-ventricular ejection fraction (LVEF), but few treatments have specifically been assessed in such patients. In previous studies of patients with CHF and low LVEF or vascular disease and preserved LVEF, inhibition of the renin-angiotensin system is beneficial. We investigated the effect of addition of an angiotensin-receptor blocker to current treatments.
Between March, 1999, and July, 2000, we randomly assigned 3023 patients candesartan (n=1514, target dose 32 mg once daily) or matching placebo (n=1509). Patients had New York Heart Association functional class II-IV CHF and LVEF higher than 40%. The primary outcome was cardiovascular death or admission to hospital for CHF. Analysis was done by intention to treat.
Median follow-up was 36.6 months. 333 (22%) patients in the candesartan and 366 (24%) in the placebo group experienced the primary outcome (unadjusted hazard ratio 0.89 [95% CI 0.77-1.03], p=0.118; covariate adjusted 0.86 [0.74-1.0], p=0.051). Cardiovascular death did not differ between groups (170 vs 170), but fewer patients in the candesartan group than in the placebo group were admitted to hospital for CHF once (230 vs 279, p=0.017) or multiple times. Composite outcomes that included non-fatal myocardial infarction and non-fatal stroke showed similar results to the primary composite (388 vs 429; unadjusted 0.88 [0.77-1.01], p=0.078; covariate adjusted 0.86 [0.75-0.99], p=0.037).
Candesartan has a moderate impact in preventing admissions for CHF among patients who have heart failure and LVEF higher than 40%.
Angiotensin-converting-enzyme (ACE) inhibitors improve outcome of patients with chronic heart failure (CHF). A substantial proportion of patients, however, experience no benefit from ACE inhibitors because of previous intolerance. We aimed to find out whether candesartan, an angiotensin-receptor blocker, could improve outcome in such patients not taking an ACE inhibitor.
Between March, 1999, and March, 2001, we enrolled 2028 patients with symptomatic heart failure and left-ventricular ejection fraction 40% or less who were not receiving ACE inhibitors because of previous intolerance. Patients were randomly assigned candesartan (target dose 32 mg once daily) or matching placebo. The primary outcome of the study was the composite of cardiovascular death or hospital admission for CHF. Analysis was by intention to treat.
The most common manifestation of ACE-inhibitor intolerance was cough (72%), followed by symptomatic hypotension (13%) and renal dysfunction (12%). During a median follow-up of 33.7 months, 334 (33%) of 1013 patients in the candesartan group and 406 (40%) of 1015 in the placebo group had cardiovascular death or hospital admission for CHF (unadjusted hazard ratio 0.77 [95% CI 0.67-0.89], p=0.0004; covariate adjusted 0.70 [0.60-0.81], p<0.0001). Each component of the primary outcome was reduced, as was the total number of hospital admissions for CHF. Study-drug discontinuation rates were similar in the candesartan (30%) and placebo (29%) groups.
Candesartan was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic chronic heart failure and intolerance to ACE inhibitors.
The condition exists and needs to be recognised, prevented, and treated
Diastolic heart failure refers to the clinical syndrome of heart failure with a preserved left ventricular ejection fraction (0.50 or more) in the absence of major valve disease.1 About a third of patients with heart failure seen by clinicians have diastolic heart failure as defined above.2 A simple classification of heart failure into systolic versus diastolic is useful because the two conditions have a distinctive pathophysiology and different prognoses.
Although diastolic heart failure is common in clinical practice worldwide,3 4 5 its existence has been questioned for several reasons. Firstly, investigators have questioned whether these patients truly have heart failure or if they actually have conditions such as obesity or pulmonary disease that can mimic heart failure.6 Doubts regarding diastolic heart failure are cast especially because the diagnosis of heart failure is partly a clinical one and prone to error. When the left ventricular ejection fraction is low the diagnosis of heart failure is seldom questioned—clinicians seem more willing to accept a diagnosis of systolic heart failure.w1 Fortunately the advent of biomarkers such plasma B-type natriuretic peptides should help confirm the presence of heart failure in patients with suspected diastolic heart failure.w2
A second area of controversy is that while investigators may agree that some patients with heart failure do have a normal ejection fraction, they doubt if the underlying mechanism …
A decreased ratio of early to late diastolic mitral inflow velocities (E/A <1.0) reflects slowing of left ventricular (LV) relaxation. This finding is widely believed to indicate significant diastolic dysfunction. However, E/A <1.0 is common during normal aging and often is not associated with symptoms of heart failure. We asked (1) whether slowed LV relaxation is associated with exercise intolerance and (2) whether tissue Doppler imaging of the early diastolic mitral annular velocity (Ea) is helpful in understanding mechanisms of exercise intolerance.
Patients (n=121) underwent echocardiography before maximal exercise testing. Fifty-nine subjects had E/A <1.0, and 36 subjects had E/Ea > or =10. Exercise capacity was similar in the population with a normal mitral inflow pattern and those with a slow relaxation pattern when E/Ea was <10. In contrast, the subjects with slow relaxation and E/Ea > or =10 had reduced exercise tolerance. Of all the echo and clinical parameters assessed, E/Ea had the best correlation with exercise capacity (r=-0.684, P<0.001) and was the strongest independent predictor of exercise capacity < or =7 METs by multivariate analysis (prevalence-corrected odds ratio=12.6, P<0.001). E/Ea continued to be strongly associated with exercise capacity in all age groups and in those with preserved or reduced systolic function.
Of the subjects with slow LV relaxation, only those with E/Ea > or =10 have objective evidence of reduced exercise tolerance. These data suggest that elevated LV filling pressures rather than slow relaxation per se reduce exercise capacity.
We conducted a prospective multicenter registry in a large metropolitan area to define the clinical characteristics, hospital course, treatment, and factors precipitating decompensation in patients hospitalized for heart failure with a normal ejection fraction (HFNEF).
The clinical profile of patients hospitalized for HFNEF has been characterized by retrospective analyses of hospital records and state data banks, with few prospective single-center studies.
Patients hospitalized for heart failure (HF) at 24 medical centers in the New York metropolitan area and found to have a left ventricular (LV) ejection fraction of > or 50% within seven days of admission were included in this registry. Patient demographics, signs and symptoms of HF, coexisting and exacerbating cardiovascular and medical conditions, treatment, laboratory tests, procedures, and hospital outcomes data were collected. Analysis by gender and race was prespecified.
Of 619 patients, 73% were women, who were on average four years older than men (72.8 +/- 14.1 years vs. 68.6 +/- 13.8 years, p < 0.001). Black non-Hispanic patients comprised 30% of the study population. They were eight years younger than other patients (66.0 +/- 14.2 years vs. 74 +/- 13.5 years p < 0.001). Co-morbid conditions and their prevalence were: hypertension, 78%; increased LV mass, 82%; diabetes, 46%; and obesity, 46%. Before clinical decompensation that precipitated hospitalization, 86% of patients had chronic symptoms compatible with New York Heart Association functional classes II to IV. Factors precipitating clinical decompensation were identified in 53% of patients. In-hospital mortality was 4.2%.
Patients hospitalized for HFNEF are most often chronically incapacitated elderly women with a history of hypertension and increased LV mass. Reasons for clinical decompensation are identified in only one-half of patients.
The purpose of this study was to investigate the effects of carvedilol on diastolic function (DF) in heart failure patients with preserved left ventricular (LV) systolic function and abnormal DF.
We randomised 113 patients with diastolic heart failure (DHF) (symptomatic, with normal systolic LV function and abnormal DF) into a double blind multi-centre study. The patients received either carvedilol or matching placebo in addition to conventional treatment. After uptitration, treatment was continued for 6 months. Two-dimensional and Doppler echocardiography were used for quantification of LV function at baseline and at follow-up. Four different DF variables were evaluated by Doppler echocardiography: mitral flow E:A ratio, deceleration time (DT), isovolumic relaxation time (IVRT) and the ratio of systolic/diastolic pulmonary venous flow velocity (pv-S/D). Primary endpoint was change in the integrated quantitative assessment of all four variables during the study.
Ninety-seven patients completed the study. A mitral flow pattern reflecting a relaxation abnormality was recorded in 95 patients. There was no effect on the primary endpoint, although a trend towards a better effect in carvedilol treated patients was noticed in patients with heart rates above 71 beats per minute. At the end of the study, there was a statistically significant improvement in E:A ratio in patients treated with carvedilol (0.72 to 0.83) vs. placebo (0.71 to 0.76), P<0.05.
Treatment with carvedilol resulted in a significant improvement in E:A ratio in patients with heart failure due to a LV relaxation abnormality. E:A ratio was found to be the most useful variable to identify diastolic dysfunction in this patient population. This effect was observed particularly in patients with higher heart rates at baseline.
Specific treatments targeting the pathophysiology of hypertensive heart disease are lacking. As aldosterone has been implicated in the genesis of myocardial fibrosis, hypertrophy, and dysfunction, we sought to determine the effects of aldosterone antagonism on myocardial function in hypertensive patients with suspected diastolic heart failure by using sensitive quantitative echocardiographic techniques in a randomized, double-blinded, placebo-controlled study.
Thirty medically treated ambulatory hypertensive patients (19 women, age 62+/-6 years) with exertional dyspnea, ejection fraction >50%, and diastolic dysfunction (E/A <1, E deceleration time >250 m/sec) and without ischemia were randomized to spironolactone 25 mg/d or placebo for 6 months. Patients were overweight (31+/-5 kg/m2) with reduced treadmill exercise capacity (6.7+/-2.1 METS). Long-axis strain rate (SR), peak systolic strain, and cyclic variation of integrated backscatter (CVIB) were averaged from 6 walls in 3 standard apical views. Mean 24-hour ambulatory blood pressure at baseline (133+/-17/80+/-7 mm Hg) did not change in either group. Values for SR, peak systolic strain, and CVIB were similar between groups at baseline and remained unchanged with placebo. Spironolactone therapy was associated with increases in SR (baseline: -1.57+/-0.46 s(-1) versus 6-months: -1.91+/-0.36 s(-1), P<0.01), peak systolic strain (-20.3+/-5.0% versus -26.9+/-4.3%, P<0.001), and CVIB (7.4+/-1.7 dB versus 8.6+/-1.7 dB, P=0.08). Each parameter was significantly greater in the spironolactone group compared with placebo at 6 months (P=0.05, P=0.02, and P=0.02, respectively), and the increases remained significant after adjusting for baseline differences. The increase in strain was independent of changes in blood pressure with intervention. The spironolactone group also exhibited reduction in posterior wall thickness (P=0.04) and a trend to reduced left atrial area (P=0.09).
Aldosterone antagonism improves myocardial function in hypertensive heart disease.
No therapy has been shown to improve survival in heart failure (HF) with a normal ejection fraction (EF). There are plausible reasons to hypothesize that statins may be of benefit in HF with a normal EF.
We evaluated 137 patients with HF and an EF > or =0.50. The effect of treatment received at study entry on survival was determined. During a follow-up of 21+/-12 months, 20 deaths were observed. Treatment with an ACE inhibitor or receptor blocker, beta-blocker, or calcium blocker had no significant effect on survival. In contrast, treatment with a statin was associated with a substantial improvement in survival (relative risk of death [95% CI] 0.22 [0.07 to 0.64]; P=0.006). Patients receiving statins had higher baseline LDL cholesterol than those not receiving statins (153+/-45 versus 98+/-33 mg/dL, P<0.01). After statin therapy, LDL cholesterol levels fell to a similar level (101+/-32 mg/dL) as in patients not receiving statins (98+/-33 mg/dL). After adjustment for differences in baseline clinical variables between groups (hypertension, diabetes, coronary artery disease, and serum creatinine), statin therapy was associated with lower mortality (adjusted relative risk of death [95% CI] 0.20 [0.06 to 0.62]; P=0.005). Similarly, after propensity matching, statin therapy was associated with improved survival (log-rank 6.12; P=0.013) and a trend toward improved survival without cardiovascular hospitalization (log-rank 3.02; P=0.082).
Statin therapy may be associated with improved survival in patients with HF and a normal EF.
Echocardiographic left atrial (LA) volume has been documented to be an independent predictor of cardiovascular events. Less is known about the predictive ability of anteroposterior LA diameter, a simpler measure of LA size obtained routinely during echocardiographic evaluation.
We investigated the prognostic value of LA diameter for incident cardiovascular events in 2804 American Indians free of clinical cardiovascular disease, valvular disease, and atrial fibrillation. Echocardiographic variables were obtained using standardized methods, and previously derived sex-specific partition values were used to define left ventricular (LV) hypertrophy indexed to height(2.7) (in meters) and LA enlargement (> 4.2 cm in men, > 3.8 cm in women). Cardiovascular events included nonfatal stroke, coronary heart disease, congestive heart failure, and fatal cardiovascular disease based on validated definitions.
During a median follow-up of 7 years, 368 events occurred. LA diameter, both as a continuous and as a categorical variable, was significantly associated with incident cardiovascular events in unadjusted analyses. In multivariable analyses that adjusted for age, sex, body mass index, hypertension, diabetes, total cholesterol-high-density lipoprotein cholesterol, smoking, renal insufficiency, LV hypertrophy, abnormal LV systolic and diastolic function, mitral annular calcification, fibrinogen, and C-reactive protein, both LA diameter (risk ratio 1.04/mm, 95% CI 1.02-1.07, P < .002) and LA enlargement (risk ratio 1.57, 95% CI 1.17-2.10, P = .002) remained independent predictors of first cardiovascular events.
In this population-based cohort, LA diameter independently predicted incident cardiovascular events after adjustment for established clinical, echocardiographic, and inflammatory risk factors. This simple measure of LA dilatation can identify individuals at heightened risk who may warrant more aggressive risk factor modification.
Left ventricular (LV) diastolic function is 1 of the determinants of exercise tolerance. However, the relation between early diastolic velocity of the mitral annulus (Ea) obtained by tissue Doppler imaging and exercise tolerance is unknown in patients with impaired LV systolic function. To investigate the feasibility of evaluating exercise tolerance using tissue Doppler imaging, we studied 53 consecutive patients (mean age 58 +/- 14 years) with a LV ejection fraction of <50% (mean 37 +/- 9%). We measured the peak early diastolic velocity of transmitral flow (E) and Ea at the lateral border of the mitral annulus and then calculated the E/Ea ratio. After echocardiography, we measured the peak oxygen consumption and anaerobic threshold (AT) by cardiopulmonary exercise testing. Of all the echocardiographic parameters, the best correlation for AT was the E/Ea ratio (r = -0.74, p <0.001). Peak oxygen consumption correlated well with Ea and the E/Ea ratio (r = 0.64 and r = -0.68, respectively, p <0.001). The AT and peak oxygen consumption did not correlate with conventional Doppler indexes. Using an AT of 8 ml/min/kg as the cutoff to separate severe exercise intolerance from normal, mild, or moderate exercise intolerance, a receiver-operating characteristic curve showed that an E/Ea ratio of >11.3 had the best combination of sensitivity (88%) and specificity (86%). Exercise tolerance correlated with the E/Ea ratio in patients with impaired LV systolic function. In conclusion, the evaluation of LV diastolic function using tissue Doppler imaging is useful for predicting exercise tolerance in patients with heart failure.
The prevalence of heart failure with preserved ejection fraction may be changing as a result of changes in population demographics and in the prevalence and treatment of risk factors for heart failure. Changes in the prevalence of heart failure with preserved ejection fraction may contribute to changes in the natural history of heart failure. We performed a study to define secular trends in the prevalence of heart failure with preserved ejection fraction among patients at a single institution over a 15-year period.
We studied all consecutive patients hospitalized with decompensated heart failure at Mayo Clinic Hospitals in Olmsted County, Minnesota, from 1987 through 2001. We classified patients as having either preserved or reduced ejection fraction. The patients were also classified as community patients (Olmsted County residents) or referral patients. Secular trends in the type of heart failure, associated cardiovascular disease, and survival were defined.
A total of 6076 patients with heart failure were discharged over the 15-year period; data on ejection fraction were available for 4596 of these patients (76 percent). Of these, 53 percent had a reduced ejection fraction and 47 percent had a preserved ejection fraction. The proportion of patients with the diagnosis of heart failure with preserved ejection fraction increased over time and was significantly higher among community patients than among referral patients (55 percent vs. 45 percent). The prevalence rates of hypertension, atrial fibrillation, and diabetes among patients with heart failure increased significantly over time. Survival was slightly better among patients with preserved ejection fraction (adjusted hazard ratio for death, 0.96; P=0.01). Survival improved over time for those with reduced ejection fraction but not for those with preserved ejection fraction.
The prevalence of heart failure with preserved ejection fraction increased over a 15-year period, while the rate of death from this disorder remained unchanged. These trends underscore the importance of this growing public health problem.
About half of the 5 million heart failure patients in the United States have diastolic heart failure (clinical heart failure with normal or near-normal ejection fraction). Except for candesartan, no drugs have been tested in randomized clinical trials in these patients. Although digoxin was tested in an appreciable number of diastolic heart failure patients in the Digitalis Investigation Group ancillary trial, detailed findings from this important study have not previously been published.
Ambulatory chronic heart failure patients (n = 988) with normal sinus rhythm and ejection fraction > 45% (median, 53%) from the United States and Canada (1991 to 1993) were randomly assigned to digoxin (n = 492) or placebo (n = 496). During follow-up with a mean length of 37 months, 102 patients (21%) in the digoxin group and 119 patients (24%) in the placebo group (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.63 to 1.07; P = 0.136) experienced the primary combined outcome of heart failure hospitalization or heart failure mortality. Digoxin had no effect on all-cause or cause-specific mortality or on all-cause or cardiovascular hospitalization. Use of digoxin was associated with a trend toward a reduction in hospitalizations resulting from worsening heart failure (HR, 0.79; 95% CI, 0.59 to 1.04; P = 0.094) but also a trend toward an increase in hospitalizations for unstable angina (HR, 1.37; 95% CI, 0.99 to 1.91; P = 0.061).
In ambulatory patients with chronic mild to moderate diastolic heart failure and normal sinus rhythm receiving angiotensin-converting enzyme inhibitor and diuretics, digoxin had no effect on natural history end points such as mortality and all-cause or cardiovascular hospitalizations.
Many patients who receive a diagnosis of heart failure have neither a low left ventricular (LV) ejection fraction nor valve disease. Few substantial randomized controlled trials have been conducted in this population, none has focussed on patients with evidence of diastolic dysfunction and none has shown clear benefit on symptoms, morbidity, or mortality.
This was a randomized double-blind trial, comparing placebo with perindopril, 4 mg/day in patients aged > or =70 years with a diagnosis of heart failure, treated with diuretics and an echocardiogram suggesting diastolic dysfunction and excluding substantial LV systolic dysfunction or valve disease. The primary endpoint was a composite of all-cause mortality and unplanned heart failure related hospitalization with a minimum follow-up of 1 year. A total of 850 patients were randomized. Their mean age was 76 (SD 5) years and 55% were women. Median follow-up was 2.1 (IQR 1.5-2.8) years. Enrollment and event rates were lower than anticipated, reducing the power of the study to show a difference in the primary endpoint to 35%. Many patients withdrew from perindopril (28%) and placebo (26%) after 1 year and started taking open-label ACE-inhibitors. Overall, 107 patients assigned to placebo and 100 assigned to perindopril reached the primary endpoint (HR 0.919: 95% CI 0.700-1.208; P = 0.545). By 1 year, reductions in the primary outcome (HR 0.692: 95% CI 0.474-1.010; P = 0.055) and hospitalization for heart failure (HR 0.628: 95% CI 0.408-0.966; P = 0.033) were observed and functional class (P < 0.030) and 6-min corridor walk distance (P = 0.011) had improved in those assigned to perindopril.
Uncertainty remains about the effects of perindopril on long-term morbidity and mortality in this clinical setting since this study had insufficient power for its primary endpoint. However, improved symptoms and exercise capacity and fewer hospitalizations for heart failure in the first year were observed on perindopril, during which most patients were on assigned therapy, suggesting that it may be of benefit in this patient population.
Nearly half of patients with heart failure have a preserved ejection fraction (HFpEF). Symptoms of exercise intolerance and dyspnea are most often attributed to diastolic dysfunction; however, impaired systolic and/or arterial vasodilator reserve under stress could also play an important role.
Patients with HFpEF (n=17) and control subjects without heart failure (n=19) generally matched for age, gender, hypertension, diabetes mellitus, obesity, and the presence of left ventricular hypertrophy underwent maximal-effort upright cycle ergometry with radionuclide ventriculography to determine rest and exercise cardiovascular function. Resting cardiovascular function was similar between the 2 groups. Both had limited exercise capacity, but this was more profoundly reduced in HFpEF patients (exercise duration 180+/-71 versus 455+/-184 seconds; peak oxygen consumption 9.0+/-3.4 versus 14.4+/-3.4 mL x kg(-1) x min(-1); both P<0.001). At matched low-level workload, HFpEF subjects displayed approximately 40% less of an increase in heart rate and cardiac output and less systemic vasodilation (all P<0.05) despite a similar rise in end-diastolic volume, stroke volume, and contractility. Heart rate recovery after exercise was also significantly delayed in HFpEF patients. Exercise capacity correlated with the change in cardiac output, heart rate, and vascular resistance but not end-diastolic volume or stroke volume. Lung blood volume and plasma norepinephrine levels rose similarly with exercise in both groups.
HFpEF patients have reduced chronotropic, vasodilator, and cardiac output reserve during exercise compared with matched subjects with hypertensive cardiac hypertrophy. These limitations cannot be ascribed to diastolic abnormalities per se and may provide novel therapeutic targets for interventions to improve exercise capacity in this disorder.
The goal of this study was to determine heart failure prevalence and incidence rates, subsequent mortality, and risk factors for heart failure among older populations in Medicare with diabetes.
We used a national 5% sample of Medicare claims from 1994 to 1999 to perform a population-based, nonconcurrent cohort study in 151,738 beneficiaries with diabetes who were age > or =65 years, not in managed care, and were alive on 1 January 1995. Prevalent heart failure was defined as a diagnosis of heart failure in 1994; incident heart failure was defined as a new diagnosis in 1995-1999 among those without prevalent heart failure. Mortality was assessed through 31 December 1999.
Heart failure was prevalent in 22.3% in 1994. Among individuals without heart failure in 1994, the heart failure incidence rate was 12.6 per 100 person-years (95% CI 12.5-12.7 per 100 person-years). Incidence was similar by sex and race and increased significantly with age and diabetes-related comorbidities. The adjusted hazard of incident heart failure increased for individuals with the following: metabolic complications of diabetes (a proxy for poor control and/or severity) (hazards ratio 1.23, 95% CI 1.18-1.29), ischemic heart disease (1.74, 1.70-1.79), nephropathy (1.55, 1.45-1.67), and peripheral vascular disease (1.35, 1.31-1.39). Over 60 months, incident heart failure among older adults with diabetes was associated with high mortality-32.7 per 100 person-years compared with 3.7 per 100 person-years among those with diabetes who remained heart failure free.
These data demonstrate alarmingly high prevalence, incidence, and mortality for heart failure in individuals with diabetes. Prevention of heart failure should be a research and clinical priority.
The purpose of this study was to identify cardiovascular features of patients with heart failure with preserved ejection fraction (HFpEF) that differ from those in individuals with hypertensive left ventricular hypertrophy (HLVH) of similar age, gender, and racial background but without failure.
Heart failure with preserved ejection fraction often develops in HLVH patients and involves multiple abnormalities. Clarification of changes most specific to HFpEF may help elucidate underlying pathophysiology.
A cross-sectional study comparing HFpEF patients (n = 37), HLVH subjects without HF (n = 40), and normotensive control subjects without LVH (n = 56). All subjects had an EF of >50%, sinus rhythm, and insignificant valvular or active ischemic disease, and groups were matched for age, gender, and ethnicity. Comprehensive echo-Doppler and pressure analysis was performed.
The HFpEF patients were predominantly African-American women with hypertension, LVH, and obesity. They had vascular and systolic-ventricular stiffening and abnormal diastolic function compared with the control subjects. However, most of these parameters either individually or combined were similarly abnormal in the HLVH group and poorly distinguished between these groups. The HFpEF group had quantitatively greater concentric LVH and estimated mean pulmonary artery wedge pressure (20 mm Hg vs. 16 mm Hg) and shorter isovolumic relaxation time than the HLVH group. They also had left atrial dilation/dysfunction unlike in HLVH and greater total epicardial volume. The product of LV mass index and maximal left atrial (LA) volume best identified HFpEF patients (84% sensitivity, 82% specificity).
In an urban, principally African American, cohort, HFpEF patients share many abnormalities of systolic, diastolic, and vascular function with nonfailing HLVH subjects but display accentuated LVH and LA dilation/failure. These latter factors may help clarify pathophysiology and define an important HFpEF population for clinical trials.
Diastolic dysfunction might represent an important pathophysiological intermediate between hypertension and heart failure. Our aim was to determine whether inhibitors of the renin-angiotensin-aldosterone system, which can reduce ventricular hypertrophy and myocardial fibrosis, can improve diastolic function to a greater extent than can other antihypertensive agents.
Patients with hypertension and evidence of diastolic dysfunction were randomly assigned to receive either the angiotensin receptor blocker valsartan (titrated to 320 mg once daily) or matched placebo. Patients in both groups also received concomitant antihypertensive agents that did not inhibit the renin-angiotensin system to reach targets of under 135 mm Hg systolic blood pressure and under 80 mm Hg diastolic blood pressure. The primary endpoint was change in diastolic relaxation velocity between baseline and 38 weeks as determined by tissue doppler imaging. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00170924.
186 patients were randomly assigned to receive valsartan; 198 were randomly assigned to receive placebo. 43 patients were lost to follow-up or discontinued the assigned intervention. Over 38 weeks, there was a 12.8 (SD 17.2)/7.1 (9.9) mm Hg reduction in blood pressure in the valsartan group and a 9.7 (17.0)/5.5 (10.2) mm Hg reduction in the placebo group. The difference in blood pressure reduction between the two groups was not significant. Diastolic relaxation velocity increased by 0.60 (SD 1.4) cm/s from baseline in the valsartan group (p<0.0001) and 0.44 (1.4) cm/s from baseline in the placebo group (p<0.0001) by week 38. However, there was no significant difference in the change in diastolic relaxation velocity between the groups (p=0.29).
Lowering blood pressure improves diastolic function irrespective of the type of antihypertensive agent used.
Hypertensive left ventricular hypertrophy (LVH) is associated with cardiomyocyte hypertrophy and an excess in myocardial collagen. Myocardial fibrosis may cause diastolic dysfunction and heart failure. Circulating levels of the carboxy-terminal propeptide of procollagen type I (PICP), an index of collagen type I synthesis, correlate with the extent of myocardial fibrosis. This study examines myocardial fibrosis in relation to blood pressure, left ventricular mass (LVM), and diastolic function.
We examined PICP levels in 115 patients with hypertensive LVH, 38 with hypertension but no hypertrophy, and 38 normotensive subjects. Patients with LVH were subsequently randomly assigned to the angiotensin II type 1 receptor blocker irbesartan or the beta1 receptor blocker atenolol for 48 weeks. Diastolic function was evaluated by tissue velocity echocardiography (n=134). We measured basal septal wall velocities of early (Em) and late (Am) diastolic myocardial wall motion, Em velocity deceleration time (E-decm), and isovolumic relaxation time (IVRTm).
Compared with the normotensive group, PICP was elevated and left ventricular diastolic function was impaired in the hypertensive groups, with little difference between patients with and without LVH. PICP related to blood pressure, IVRTm, Em, and E/Em, but not to LVM. Irbesartan and atenolol reduced PICP similarly. Only in the irbesartan group did changes in PICP relate to changes in IVRTm, and LVM.
Myocardial fibrosis and diastolic dysfunction are present in hypertension before LVH develops. The findings with irbesartan suggest a role for angiotensin II in the control of myocardial fibrosis and diastolic function in patients with hypertension with LVH.
This article presents a series of take-home statements, compiled by a multidisciplinary steering committee, concerning significant aspects of macrovascular disease in patients with diabetes mellitus, including the extent of risk, pathogenetic mechanisms, and optimal management for risk reduction. The discussion focuses in particular on the impact of diabetes medications beyond blood glucose control. In summary, these statements are as follows: (1) Patients with diabetes have an increased risk for cardiovascular disease that contributes to decreased life expectancy; (2) prognosis after a cardiovascular event is poorer in patients with diabetes; (3) pathogenetic mechanisms include insulin resistance, endothelial dysfunction, dyslipidemia, chronic inflammation, procoagulability, and impaired fibrinolysis; (4) management of established cardiovascular risk factors, for example with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and antihypertensive therapy, reduces cardiovascular event rates in diabetes; (5) correction of hyperglycemia can reduce macrovascular event rates, but the coupling to hyperglycemia is less tight for macrovascular events than it is for reduction of microvascular complications; (6) patients with diabetes should be screened for additional cardiovascular risk factors and appropriate interventions should be initiated; (7) results of observational and interventional studies have indicated that some insulin sensitizers appear to reduce the incidence of cardiovascular events and improve survival; (8) thiazolidinediones have beneficial effects on metabolism that may improve cardiovascular risk, and a randomized clinical trial in patients with advanced atherosclerosis indicates that addition of pioglitazone to therapy for hyperglycemia may reduce the incidence of cardiovascular events such as myocardial infarction and stroke.
Excessive diastolic left ventricular stiffness is an important contributor to heart failure in patients with diabetes mellitus. Diabetes is presumed to increase stiffness through myocardial deposition of collagen and advanced glycation end products (AGEs). Cardiomyocyte resting tension also elevates stiffness, especially in heart failure with normal left ventricular ejection fraction (LVEF). The contribution to diastolic stiffness of fibrosis, AGEs, and cardiomyocyte resting tension was assessed in diabetic heart failure patients with normal or reduced LVEF.
Left ventricular endomyocardial biopsy samples were procured in 28 patients with normal LVEF and 36 patients with reduced LVEF, all without coronary artery disease. Sixteen patients with normal LVEF and 10 with reduced LVEF had diabetes mellitus. Biopsy samples were used for quantification of collagen and AGEs and for isolation of cardiomyocytes to measure resting tension. Diabetic heart failure patients had higher diastolic left ventricular stiffness irrespective of LVEF. Diabetes mellitus increased the myocardial collagen volume fraction only in patients with reduced LVEF (from 14.6+/-1.0% to 22.4+/-2.2%, P<0.001) and increased cardiomyocyte resting tension only in patients with normal LVEF (from 5.1+/-0.7 to 8.5+/-0.9 kN/m2, P=0.006). Diabetes increased myocardial AGE deposition in patients with reduced LVEF (from 8.8+/-2.5 to 24.1+/-3.8 score/mm2; P=0.005) and less so in patients with normal LVEF (from 8.2+/-2.5 to 15.7+/-2.7 score/mm2, P=NS).
Mechanisms responsible for the increased diastolic stiffness of the diabetic heart differ in heart failure with reduced and normal LVEF: Fibrosis and AGEs are more important when LVEF is reduced, whereas cardiomyocyte resting tension is more important when LVEF is normal.