Zakeri, Rosita

Background— Left atrial (LA) structure and function are altered in most heart failure (HF) patients, but there may be fundamental differences in LA properties between HF with preserved (HFpEF) and reduced ejection fraction (HFrEF). Methods and Results— One hundred ninety-eight HF patients (51% HFpEF, New York Heart Association 3.1±0.7) and 40 HF-free controls underwent catheterization, echocardiography, and follow-up. Compared with controls, HF patients had larger and more dysfunctional left atria. At identical mean LA pressure (20 versus 20 mm Hg; P =0.9), HFrEF patients had larger LA volumes (LA volume index 50 versus 41 mL/m 2 ; P <0.001), whereas HFpEF patients had higher LA peak pressures, lower LA minimal pressures, higher LA stiffness (0.79 versus 0.48 mm Hg/mL; P <0.001), greater LA pulsatility (19 versus 13 mm Hg; P <0.001), and higher wall stress variations. Despite smaller LA volumes, better function, and less mitral regurgitation, HFpEF patients had more atrial fibrillation (42 versus 26%; P =0.02). LA dysfunction was associated with increased pulmonary vascular resistance and right ventricular dysfunction in both HF phenotypes. After a median follow-up of 350 days, 31 HFpEF and 28 HFrEF patients died. LA function (total LA EF) was associated with lower mortality in HFpEF (hazard ratio 0.43; 95% confidence interval, 0.2–0.9; P <0.05), but not in HFrEF. Conclusions— HFrEF is characterized by greater eccentric LA remodeling, whereas HFpEF by increased LA stiffness, which might contribute to greater atrial fibrillation burden. LA function is associated with pulmonary vascular disease and right HF in both HF phenotypes, but is associated with outcome more closely in HFpEF, supporting efforts to improve LA function in this cohort.

Background— Exercise intolerance is a hallmark of heart failure, but factors associated with impaired exercise capacity in heart failure with preserved ejection fraction are unclear. We hypothesized that in heart failure with preserved ejection fraction, the severity of resting ventricular and vascular dysfunction are associated with impairment in exercise tolerance as assessed by peak oxygen consumption. Methods and Results— Subjects with heart failure with preserved ejection fraction enrolled in the PhosphodiesteRasE-5 Inhibition to Improve CLinical Status And EXercise Capacity in Diastolic Heart Failure (RELAX) clinical trial (n=216) underwent baseline Doppler echocardiography, cardiopulmonary exercise testing, and cardiac MRI. RELAX participants were elderly (median age 69 years) and 48% were women. Ejection fraction (60%) and stroke volume (77 mL) were normal, while diastolic dysfunction (medial E / e ′, 16; deceleration time, 185 ms; left atrial volume, 44 mL/m 2 ) and increased arterial load (arterial elastance, 1.51 mm Hg/mL) were evident. Peak oxygen consumption was reduced (11.7 mLkg −1 min −1 , 1141 mL/min) and age, sex, body mass index, hemoglobin, and chronotropic response collectively explained 64% of the variance in raw peak oxygen consumption (mL/min). After adjustment for these variables, left ventricular structure (diastolic dimension [1.5%, P =0.008] and left ventricular mass [1.6%, P =0.008]), resting stroke volume (2.0%, P =0.002), left ventricular diastolic dysfunction (deceleration time [0.9%, P =0.03] and E / e ′ [1.4%, P =0.009]), and arterial function (arterial elastance [2.1%, P =0.002] and systemic arterial compliance [1.5%, P =0.007]), each explained only a small additional portion of the variance in peak oxygen consumption. Conclusions— In heart failure with preserved ejection fraction, potentially modifiable factors (obesity, anemia, and chronotropic incompetence) are strongly associated with exercise capacity, whereas resting measures of ventricular and vascular structure and function are not. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00763867

Background— Atrial fibrillation (AF) is common among patients with heart failure and preserved ejection fraction (HFpEF), but its clinical profile and impact on exercise capacity remain unclear. RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF) was a multicenter randomized trial testing the impact of sildenafil on peak V O 2 in stable outpatients with chronic HFpEF. We sought to compare clinical features and exercise capacity among patients with HFpEF who were in sinus rhythm (SR) or AF. Methods and Results— RELAX enrolled 216 patients with HFpEF, of whom 79 (37%) were in AF, 124 (57%) in SR, and 13 in other rhythms. Participants underwent baseline cardiopulmonary exercise testing, echocardiogram, biomarker assessment, and rhythm status assessment before randomization. Patients with AF were older than those in SR but had similar symptom severity, comorbidities, and renal function. β-blocker use and chronotropic indices were also similar. Despite comparable left ventricular size and mass, AF was associated with worse systolic (lower EF, stroke volume, and cardiac index) and diastolic (shorter deceleration time and larger left atria) function compared with SR. Pulmonary artery systolic pressure was higher in AF. Patients with AF had higher N-terminal pro-B-type natriuretic peptide, aldosterone, endothelin-1, troponin I, and C-telopeptide for type I collagen levels, suggesting more severe neurohumoral activation, myocyte necrosis, and fibrosis. Peak V O 2 was lower in AF, even after adjustment for age, sex, and chronotropic response, and V E /V CO 2 was higher. Conclusions— AF identifies an HFpEF cohort with more advanced disease and significantly reduced exercise capacity. These data suggest that evaluation of the impact of different rate or rhythm control strategies on exercise tolerance in patients with HFpEF and AF is warranted. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00763867.

Background— In patients with heart failure and preserved ejection fraction (HFpEF), atrial fibrillation (AF) may predate, concur with, or develop after HFpEF diagnosis. We sought to define the temporal relationship between AF and HFpEF, to identify factors associated with AF, and to determine the prognostic impact of prevalent and incident AF in HFpEF. Method and Results— From 1983 to 2010, 939 Olmsted County, Minnesota, residents (age, 77±12 years; 61% female) newly diagnosed with HFpEF (EF ≥0.50) were evaluated. Baseline rhythm classification included prior AF (>3 months before HFpEF diagnosis), concurrent AF (±3 months), or sinus rhythm. Incident AF (>3 months after HFpEF diagnosis) and all-cause mortality were ascertained through February 2012. Prior AF (29%) and concurrent AF (23%) were associated with older age, higher brain-type natriuretic peptide, and larger left atrial volume index at HFpEF diagnosis compared with sinus rhythm. Of HFpEF patients in sinus rhythm at diagnosis, 32% developed AF over a median follow-up of 3.7 years (interquartile range, 1.5–6.7 years; 69 events per 1000 person-years). Age and diastolic dysfunction were positively and statin use was inversely associated with incident AF. With no AF used as the referent, prior or concurrent AF (combined hazard ratio, 1.3; 95% confidence interval, 1.0–1.6; P =0.03) and incident AF, modeled as a time-dependent covariate (hazard ratio, 2.1; 95% confidence interval, 1.4–3.0; P <0.001), were independently associated with death after adjustment for pertinent covariates. Conclusions— AF occurs in two thirds of HFpEF patients at some point in the natural history and confers a poor prognosis. Further study is required to determine whether intervention for AF may improve outcomes or if statin use can prevent AF in HFpEF.

Despite recent pharmacological advances in heart failure therapy, mortality from acute decompensated heart failure remains high. Conventional therapies are often insufficient to address the complex interplay between structural, functional, neurohumoral, and renal mechanisms involved in the heart failure syndrome. The natriuretic peptide system, however, offers a unique pleiotropic strategy which could bridge this gap in heart failure therapy. Exogenous administration of native A-type and B-type natriuretic peptides has been met with both success and limitations, and despite the limitations, remains a worthwhile endeavor. Alternatively, synthetic modification to create “designer” chimeric peptides holds the possibility to extend both the application and therapeutic benefits possible with a natriuretic peptide based approach. Herein we describe the development of natriuretic peptide based heart failure therapies, including the design, rationale, and preliminary studies of the novel chimeric peptides CD-NP and CU-NP.