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Effect of Spironolactone on Exercise Tolerance and Arterial Function in Older Adults with Heart Failure with Preserved Ejection Fraction.

ABSTRACT: OBJECTIVES:To evaluate the effects of an aldosterone antagonist on exercise intolerance in older adults with heart failure and preserved ejection fraction (HFpEF). DESIGN:Randomized, placebo-controlled, double-blind trial. SETTING:Academic medical center, Winston-Salem, North Carolina. PARTICIPANTS:Older adults (N = 80, aged 71 ± 1; 80% female) with stable compensated HFpEF and controlled blood pressure (BP). MEASUREMENTS:Participants were randomized into a 9-month treatment of spironolactone 25 mg/d vs placebo. Assessments were peak exercise oxygen consumption (VO2 ), 6-minute walk test, Minnesota Living with Heart Failure Questionnaire (MLHFQ), cardiac magnetic resonance imaging, Doppler echocardiography, and vascular ultrasound. RESULTS:Seventy-one participants completed the trial: 37 in the spironolactone group and 34 in the placebo group. Adherence according to pill count was excellent (spironolactone 95%, placebo 97%). Mean spironolactone dose was 24.3 ± 2.9 mg/d and was well tolerated. Spironolactone significantly reduced systolic and diastolic BP at rest and peak exercise. At 9-month follow-up, baseline-adjusted peak VO2, the primary outcome, was 13.5 ± 0.3 mL/kg per minute in the spironolactone group versus 13.9 ± 0.3 mL/kg per minute in the placebo group (adjusted mean difference -0.4 mL/kg per minute; 95% confidence interval = -1.1-0.4 mL/kg per minute; P = .38). The 95% confidence intervals of spironolactone's effect on peak VO2 (-8.2% to 3.2%) excluded a clinically significant beneficial effect. There were also no significant differences in 6-minute walk distance, arterial stiffness, left ventricular (LV) mass, LV mass/end-diastolic volume, or MLHFQ score. CONCLUSION:In older adults with stable compensated HFpEF, 9 months of spironolactone 25 mg/d was well tolerated and reduced BP but did not improve exercise capacity, quality of life, LV mass, or arterial stiffness.

SUBMITTER: Upadhya B

PROVIDER: S-EPMC5681414 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Effect of Spironolactone on Exercise Tolerance and Arterial Function in Older Adults with Heart Failure with Preserved Ejection Fraction.

Upadhya Bharathi B Hundley William G WG Brubaker Peter H PH Morgan Timothy M TM Stewart Kathryn P KP Kitzman Dalane W DW

Journal of the American Geriatrics Society 20170519 11

<h4>Objectives</h4>To evaluate the effects of an aldosterone antagonist on exercise intolerance in older adults with heart failure and preserved ejection fraction (HFpEF).<h4>Design</h4>Randomized, placebo-controlled, double-blind trial.<h4>Setting</h4>Academic medical center, Winston-Salem, North Carolina.<h4>Participants</h4>Older adults (N = 80, aged 71 ± 1; 80% female) with stable compensated HFpEF and controlled blood pressure (BP).<h4>Measurements</h4>Participants were randomized into a 9- ...[more]

PMID: 28542926

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Project description:BackgroundAortic stiffening and reduced nitric oxide (NO) availability may contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF).ObjectivesThis study compared indices of arterial stiffness at rest and during exercise in subjects with HFpEF and hypertensive control subjects to examine their relationships to cardiac hemodynamics and determine whether exertional arterial stiffening can be mitigated by inorganic nitrite.MethodsA total of 22 hypertensive control subjects and 98 HFpEF subjects underwent hemodynamic exercise testing with simultaneous expired gas analysis to measure oxygen consumption. Invasively measured radial artery pressure waveforms were converted to central aortic waveforms by transfer function to assess integrated measures of pulsatile aortic load, including arterial compliance, resistance, elastance, and wave reflection.ResultsArterial load and wave reflections in HFpEF were similar to those in control subjects at rest. During submaximal exercise, HFpEF subjects displayed reduced total arterial compliance and higher effective arterial elastance despite similar mean arterial pressures in control subjects. This was directly correlated with higher ventricular filling pressures and depressed cardiac output reserve (both p < 0.0001). With peak exercise, increased wave reflections, impaired compliance, and increased resistance and elastance were observed in subjects with HFpEF. A subset of HFpEF subjects (n = 52) received sodium nitrite or placebo therapy in a 1:1 double-blind, randomized fashion. Compared to placebo, nitrite decreased aortic wave reflections at rest and improved arterial compliance and elastance and central hemodynamics during exercise.ConclusionsAbnormal pulsatile aortic loading during exercise occurs in HFpEF independent of hypertension and is correlated with classical hemodynamic derangements that develop with stress. Inorganic nitrite mitigates arterial stiffening with exercise and improves hemodynamics, indicating that arterial stiffening with exercise is at least partially reversible. Further study is required to test effects of agents that target the NO pathway in reducing arterial stiffness in HFpEF. (Study of Exercise and Heart Function in Patients With Heart Failure and Pulmonary Vascular Disease [EXEC]; NCT01418248. Acute Effects of Inorganic Nitrite on Cardiovascular Hemodynamics in Heart Failure With Preserved Ejection Fraction; NCT01932606. Inhaled Sodium Nitrite on Heart Failure With Preserved Ejection Fraction; NCT02262078).

Project description:AimsVisceral adipose tissue (AT) promotes inflammation and may be associated with disease progression in heart failure with preserved ejection fraction (HFpEF). We characterized regional AT distribution in HFpEF patients and controls and analysed associations with co-morbidities and exercise tolerance.Methods and resultsMagnetic resonance imaging was performed to quantify epicardial, liver, abdominal, and thigh skeletal muscle AT. We assessed New York Heart Association (NYHA) class, 6 min walk distance, and global well-being score. Multivariable linear regression models adjusting for body surface area were used. We studied 55 HFpEF patients (41 women, mean age 67 ± 11 years) and 33 controls (21 women, mean age 57 ± 10 years). Epicardial AT (median [interquartile range] 4.6 [2.0] vs. 3.2 [1.4] mm, P < 0.001), thigh intermuscular fat (11.0 [11.5] vs. 5.0 [2.7] cm2 , P < 0.001) and liver fat fraction (6.4% [6.1] vs. 4.1% [5.5], P = 0.001) were higher in HFpEF patients than controls. Women with HFpEF had higher abdominal and thigh subcutaneous AT than men. Greater thigh intermuscular fat was associated with higher blood pressure (β [SE] 0.73 [0.17], P < 0.001) and diabetes (odds ratio [95% confidence interval] 1.2 [1.0-1.5], P = 0.03). Greater thigh intramuscular fat was associated with both worse NYHA class (β [SE] 2.7 [1.0], P = 0.01) and shorter 6 min walk distance (β [SE] -4.1 [1.9], P = 0.03), and greater epicardial AT (β [SE] -0.2 [0.1], P < 0.001) and liver fat fraction (β [SE] -0.4 [0.2], P = 0.04) were associated with lower global well-being score.ConclusionsHeart failure with preserved ejection fraction patients have increased epicardial, liver, and skeletal muscle fat compared with controls out of proportion to their increased body size, and adiposity was associated with worse NYHA class and exercise tolerance in HFpEF. These results provide the basis for further investigation into the effect of interventions to reduce regional AT distribution in relation to HFpEF symptoms and pathophysiology.

Project description:BACKGROUND:Albuminuria predicts adverse events in heart failure with preserved ejection fraction. No therapies to date have reduced albuminuria in heart failure with preserved ejection fraction. METHODS AND RESULTS:We analyzed 1175 participants from the Americas from the TOPCAT study (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) with urinary albumin:creatinine ratio (UACR) measurements at baseline. We examined the association of UACR with the primary outcome (cardiovascular death, aborted cardiac arrest, or heart failure hospitalization) and its individual components, all-cause mortality, and several safety end points using multivariable-adjusted Cox regression. We evaluated whether spironolactone reduced albuminuria at the 1-year visit in a subpopulation (N=744). Thirty-five percent had microalbuminuria, 13% had macroalbuminuria, and 80% were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Increasing UACR was associated with male sex, higher systolic blood pressure, diabetes mellitus, and renal dysfunction. Macroalbuminuria (hazard ratio, 1.67; 95% CI, 1.22-2.28) and microalbuminuria (hazard ratio, 1.47; 95% CI, 1.15-1.86) were independently associated with the TOPCAT primary end point (compared with normoalbuminuria). Adjusting for placebo response, spironolactone reduced albuminuria by 39% in all participants at the 1-year visit compared with baseline (geometric mean ratio, 0.61; 95% CI, 0.49-0.77) and by 76% (geometric mean ratio, 0.24; 95% CI, 0.10-0.56) among those with macroalbuminuria. Reducing UACR by 50% was independently associated with a reduction in heart failure hospitalization (hazard ratio, 0.90; P=0.017) and all-cause mortality (hazard ratio, 0.91; P=0.019). The change in UACR was significantly associated with change in systolic blood pressure ( P=0.001). CONCLUSIONS:In TOPCAT, albuminuria was independently associated with worse cardiovascular outcomes. Spironolactone significantly reduced albuminuria compared with placebo. Reducing albuminuria was independently associated with improved outcomes. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov . Unique identifier: NCT00094302.

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Effect of Spironolactone on Exercise Tolerance and Arterial Function in Older Adults with Heart Failure with Preserved Ejection Fraction.

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Effect of Spironolactone on Exercise Tolerance and Arterial Function in Older Adults with Heart Failure with Preserved Ejection Fraction.

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