Biomarkers in acutely decompensated heart failure with preserved or reduced ejection fraction
ABSTRACT Acute decompensated heart failure (ADHF) occurs with preserved (heart failure with preserved ejection fraction [HFpEF] ≥50%) or reduced (heart failure with reduced ejection fraction [HFrEF] <50%) ejection fraction. Natriuretic peptide (NP) levels are lower in HFpEF than HFrEF. We hypothesized that lower NP levels in HFpEF may be associated with other differences in biomarkers, specifically, renin-angiotensin-aldosterone system (RAAS) activation, oxidative stress, and a biomarker that reflects collagen synthesis.
In this prespecified ancillary analysis of patients with ADHF enrolled in the Diuretic Optimization Strategies Evaluation study, clinical features and N-terminal pro-B-type NP, cystatin C, plasma renin activity, aldosterone, oxidative stress (uric acid), and procollagen type III N-terminal peptide were compared in HFpEF and HFrEF at enrollment and 60-day follow-up.
Compared with HFrEF (n = 219), HFpEF (n = 81) patients were older, heavier, more commonly female, less treated with RAAS antagonists, but with similar New York Heart Association class, jugular venous pressure, and edema severity. N-terminal pro-B-type NP was lower, and systolic blood pressure and cystatin C were higher in HFpEF. Despite higher systolic blood pressure and less RAAS antagonist use in HFpEF, plasma renin activity and aldosterone levels were similar in HFpEF and HFrEF as were uric acid and procollagen type III N-terminal peptide levels. Changes in biomarker levels from enrollment to 60 days were similar between HFrEF (n = 149) and HFpEF (n = 50).
Lower NP levels in decompensated HFpEF occur in association with similar ADHF severity, more impaired vascular and renal function but similar elevation of biomarkers that reflect RAAS activation, oxidative stress, and collagen synthesis as in HFrEF.
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ABSTRACT: BACKGROUND: -Heart failure (HF) can occur in patients with preserved (HFpEF, EF≥50%) or reduced (HFrEF, EF<50%) ejection fraction (EF), but changes in EF after HF diagnosis are not well described. METHODS AND RESULTS: -Among a community cohort of incident HF patients diagnosed from 1984-2009 in Olmsted County, Minnesota, we obtained all EFs assessed by echocardiography from initial HF diagnosis until death or last follow-up through March 2010. Mixed effects models fit a unique linear regression line for each person using serial EF data. Compiled results allowed estimates of the change in EF over time in HFpEF and HFrEF. Among 1233 HF patients (48.3% male, mean age 75.0 years, mean follow-up 5.1 years), 559 (45.3%) had HFpEF at diagnosis. In HFpEF, on average, EF decreased by 5.8% over 5 years (p<0.001) with greater declines in older individuals and those with coronary disease. Conversely, EF increased in HFrEF (average increase 6.9% over 5 years, p<0.001). Greater increases were noted in women, younger patients, individuals without coronary disease, and those treated with evidence-based medications. Overall, 39% of HFpEF patients had an EF<50% and 39% of HFrEF patients had an EF≥50% at some point after diagnosis. Decreases in EF over time were associated with reduced survival while increases in EF were associated with improved survival. CONCLUSIONS: -These data suggest that progressive contractile dysfunction may contribute to the pathophysiology of HFpEF. Prospective longitudinal studies are needed to confirm these observations and establish the mechanism and clinical relevance of decline in EF over time in HFpEF.Circulation Heart Failure 08/2012; 5(6). DOI:10.1161/CIRCHEARTFAILURE.111.966366 · 5.95 Impact Factor
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ABSTRACT: IMPORTANCE Studies in experimental and human heart failure suggest that phosphodiesterase-5 inhibitors may enhance cardiovascular function and thus exercise capacity in heart failure with preserved ejection fraction (HFPEF). OBJECTIVE To determine the effect of the phosphodiesterase-5 inhibitor sildenafil compared with placebo on exercise capacity and clinical status in HFPEF. DESIGN Multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial of 216 stable outpatients with HF, ejection fraction ≥50%, elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity. Participants were randomized from October 2008 through February 2012 at 26 centers in North America. Follow-up was through August 30, 2012. INTERVENTIONS Sildenafil (n = 113) or placebo (n = 103) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks. MAIN OUTCOME MEASURES Primary end point was change in peak oxygen consumption after 24 weeks of therapy. Secondary end points included change in 6-minute walk distance and a hierarchical composite clinical status score (range, 1-n, a higher value indicates better status; expected value with no treatment effect, 95) based on time to death, time to cardiovascular or cardiorenal hospitalization, and change in quality of life for participants without cardiovascular or cardiorenal hospitalization at 24 weeks. RESULTS Median age was 69 years, and 48% of patients were women. At baseline, median peak oxygen consumption (11.7 mL/kg/min) and 6-minute walk distance (308 m) were reduced. The median E/e' (16), left atrial volume index (44 mL/m2), and pulmonary artery systolic pressure (41 mm Hg) were consistent with chronically elevated left ventricular filling pressures. At 24 weeks, median (IQR) changes in peak oxygen consumption (mL/kg/min) in patients who received placebo (-0.20 [IQR, -0.70 to 1.00]) or sildenafil (-0.20 [IQR, -1.70 to 1.11]) were not significantly different (P = .90) in analyses in which patients with missing week-24 data were excluded, and in sensitivity analysis based on intention to treat with multiple imputation for missing values (mean between-group difference, 0.01 mL/kg/min, [95% CI, -0.60 to 0.61]). The mean clinical status rank score was not significantly different at 24 weeks between placebo (95.8) and sildenafil (94.2) (P = .85). Changes in 6-minute walk distance at 24 weeks in patients who received placebo (15.0 m [IQR, -26.0 to 45.0]) or sildenafil (5.0 m [IQR, -37.0 to 55.0]; P = .92) were also not significantly different. Adverse events occurred in 78 placebo patients (76%) and 90 sildenafil patients (80%). Serious adverse events occurred in 16 placebo patients (16%) and 25 sildenafil patients (22%). CONCLUSION AND RELEVANCE Among patients with HFPEF, phosphodiesterase-5 inhibition with administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00763867.JAMA The Journal of the American Medical Association 03/2013; DOI:10.1001/jama.2013.2024 · 30.39 Impact Factor
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ABSTRACT: Over the last decennium, myocardial structure, cardiomyocyte function and intramyocardial signaling were shown to be specifically altered in heart failure with preserved ejection fraction (HFPEF). A new paradigm for HFPEF development is therefore proposed, which identifies a systemic proinflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations. The new paradigm presumes the following sequence of events in HFPEF: 1) A high prevalence of comorbidities such as overweight/obesity, diabetes mellitus, chronic obstructive pulmonary disease and salt sensitive hypertension induce a systemic proinflammatory state; 2) A systemic proinflammatory state causes coronary microvascular endothelial inflammation; 3) Coronary microvascular endothelial inflammation reduces nitric oxide (NO) bioavailability, cyclic guanosine monophosphate (cGMP) content and protein kinase G (PKG) activity in adjacent cardiomyocytes; 4) Low PKG activity favours hypertrophy development and raises resting tension because of hypophosphorylation of titin; 5) Both stiff cardiomyocytes and interstitial fibrosis contribute to high diastolic left ventricular (LV) stiffness and HF development. The new HFPEF paradigm shifts emphasis from left ventricular (LV) afterload excess to coronary microvascular inflammation. This shift is supported by a favourable Laplace relationship in concentric LV hypertrophy and by all cardiac chambers showing similar remodeling and dysfunction. Myocardial remodeling in HFPEF differs from heart failure with reduced ejection fraction (HFREF), where remodeling is driven by loss of cardiomyocytes. The new HFPEF paradigm proposes comorbidities, plasma markers of inflammation or vascular hyperaemic responses to be included in diagnostic algorithms and aims at restoring myocardial PKG activity with NO-donors, phosphodiesterase 5 inhibitors and statins.Journal of the American College of Cardiology 05/2013; 62(4). DOI:10.1016/j.jacc.2013.02.092 · 15.34 Impact Factor