Rosita Zakeri

Relation between mild renal dysfunction and outcomes after coronary artery bypass grafting

Background—Risk stratification algorithms for coronary artery bypass grafting (CABG) do not include a weighting for preoperative mild renal impairment defined as a serum creatinine 130 to 199 &mgr;mol/L (1.47 to 2.25 mg/dL), which may impact mortality and morbidity after CABG. Methods and Results—We reviewed prospectively collected data between 1997 and 2004 on 4403 consecutive patients undergoing first-time isolated CABG with a preoperative serum creatinine <200 &mgr;mol/L (2.26 mg/dL)] in a single institution. The in-hospital mortality was 2.5% (112 of 4403), the need for new dialysis/hemofiltration was 1.3% (57 of 4403), and the stroke rate was 2.5% (108 of 4403). There were 458 patients with a serum creatinine 130 to 199 &mgr;mol/L or 1.47 to 2.25 mg/dL (mild renal dysfunction group) and 3945 patients with a serum creatinine <130 &mgr;mol/L (<1.47 mg/dL). Operative mortality was higher in the mild renal dysfunction group (2.1% versus 6.1%; P<0.001) and increased with increasing preoperative serum creatinine level. New dialysis/hemofiltration (0.8%versus 5.2%; P<0.001) and postoperative stroke (2.2% versus 5.0%; P<0.01) were also more common in the patients with mild renal impairment. Multivariate analysis adjusting for known risk factors confirmed preoperative mild renal impairment (creatinine 130 to 199 &mgr;mol/L or 1.47 to 2.25 mg/dL; odd ratio, 1.91; 95% CI, 1.18 to 3.03; P=0.007) or glomerular filtration rate estimates <60 mL/min per 1.73 m2, derived using the Cockroft-Gault formula, (odds ratio, 1.98; 95% CI, 1.16 to 3.48; P=0.015) as independent predictors of in-hospital mortality. Preoperative mild renal dysfunction adversely affected the 3-year survival probability after CABG (93% versus 81%; P<0.001). Conclusions—Mild renal dysfunction is an important predictor of outcome in terms of in-hospital mortality, morbidity, and midterm survival in patients undergoing CABG.

Left Atrial Remodeling and Function in Advanced Heart Failure With Preserved or Reduced Ejection Fraction

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/m2; 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.

Temporal Relationship and Prognostic Significance of Atrial Fibrillation in Heart Failure Patients with Preserved Ejection Fraction: A Community-Based Study

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.

Impact of Atrial Fibrillation on Exercise Capacity in Heart Failure with Preserved Ejection Fraction: A RELAX Trial Ancillary Study

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 VO2 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. &bgr;-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 VO2 was lower in AF, even after adjustment for age, sex, and chronotropic response, and VE/VCO2 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.

Nitrate’s Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction Trial Rationale and Design

The prevalence of heart failure (HF) with preserved ejection fraction (HFpEF) is increasing.1 In patients with HFpEF, the burden of symptoms, functional decline, and mortality is high,2 and health-related quality of life is poor.3 Physicians caring for these patients currently have limited therapeutic options beyond diuresis and management of comorbid conditions. Hence there remains an immediate and critical need for therapies to alleviate symptoms and meaningfully improve quality of life for patients with HFpEF. Long-acting nitrates are used as the cornerstone of antianginal therapy and have demonstrated beneficial effects for treatment of patients with HF and reduced EF (HFrEF). In randomized studies, sustained increases in treadmill exercise time4,5 and peak oxygen consumption6 have been observed at 3 months after initiation of nitrate therapy in patients with HFrEF, including those already treated with angiotensin converting enzyme inhibitors.5 Attenuation of pathological left ventricular (LV) remodeling and improved LV systolic function have also been reported.5 Although no study has directly examined the effects of nitrate monotherapy on survival in HF, symptom relief is a key management goal in patients with HFpEF, whose primary chronic symptom is often exercise limitation.7 Practice guidelines for the management of chronic HF from the American College of Cardiology/American Heart Association8 and Heart Failure Society of America9 advocate a potential role for nitrates in diminishing symptoms in HFpEF but acknowledge the lack of supportive data and the risk of excessive nitrate–induced hypotension in elderly patients with HFpEF. Therefore, it is desirable that a randomized, controlled evaluation of the efficacy and tolerance of nitrate therapy in HFpEF is performed to support its therapeutic applications. To address this lack of data and current clinical equipoise for nitrate therapy in HFpEF, the Nitrate’s Effect on Activity Tolerance in Heart Failure …

Resting Ventricular-Vascular Function and Exercise Capacity in Heart Failure with Preserved Ejection Fraction: A RELAX Trial Ancillary Study

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/m2) and increased arterial load (arterial elastance, 1.51 mm Hg/mL) were evident. Peak oxygen consumption was reduced (11.7 mLkg−1min−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

The Emperor's New Clothes: PDE5 and the Heart

Phosphodiesterase-5 (PDE5) is highly expressed in the pulmonary vasculature, but its expression in the myocardium is controversial. Cyclic guanosine monophosphate (cGMP) activates protein kinase G (PKG), which has been hypothesized to blunt cardiac hypertrophy and negative remodeling in heart failure. Although PDE5 has been suggested to play a significant role in the breakdown of cGMP in cardiomyocytes and hence PKG regulation in the myocardium, the RELAX trial, which tested effect of PDE5 inhibition on exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF) failed to show a beneficial effect. These results highlight the controversy regarding the role and expression of PDE5 in the healthy and failing heart. This study used one- and two-dimensional electrophoresis and Western blotting to examine PDE5 expression in mouse (before and after trans-aortic constriction), dog (control and HFpEF) as well as human (healthy and failing) heart. We were unable to detect PDE5 in any cardiac tissue lysate, whereas PDE5 was present in the murine and bovine lung samples used as positive controls. These results indicate that if PDE5 is expressed in cardiac tissue, it is present in very low quantities, as PDE5 was not detected in either humans or any model of heart failure examined. Therefore in cardiac muscle, it is unlikely that PDE5 is involved the regulation of cGMP-PKG signaling, and hence PDE5 does not represent a suitable drug target for the treatment of cardiac hypertrophy. These results highlight the importance of rigorous investigation prior to clinical trial design.

Left Atrial Remodeling and Atrioventricular Coupling in a Canine Model of Early Heart Failure With Preserved Ejection Fraction

Background—Left atrial (LA) compliance and contractility influence left ventricular stroke volume. We hypothesized that diminished LA compliance and contractile function occur early during the development of heart failure with preserved ejection fraction (HFpEF) and impair overall cardiac performance. Methods and Results—Cardiac magnetic resonance imaging, echocardiography, left ventricular and LA pressure-volume studies, and tissue analyses were performed in a model of early HFpEF (elderly dogs, renal wrap-induced hypertension, exogenous aldosterone; n=9) and young control dogs (sham surgery; n=13). Early HFpEF was associated with LA enlargement, cardiomyocyte hypertrophy, and enhanced LA contractile function (median active emptying fraction 16% [95% confidence interval, 13–24]% versus 12 [10–14]%, P=0.008; end-systolic pressure-volume relationship slope 2.4 [1.9–3.2]mm Hg/mL HFpEF versus 1.5 [1.2–2.2]mm Hg/mL controls, P=0.01). However, atrioventricular coupling was impaired and the curvilinear LA end-reservoir pressure-volume relationship was shifted upward/leftward in HFpEF (LA stiffness constant [&bgr;LA] 0.16 [0.11–0.18]mm Hg/mL versus 0.06 [0.04–0.10]mm Hg/mL controls; P=0.002), indicating reduced LA compliance. Impaired atrioventricular coupling and lower LA compliance correlated with lower left ventricular stroke volume. Total fibrosis and titin isoform composition were similar between groups; however, titin was hyperphosphorylated in HFpEF and correlated with &bgr;LA. LA microvascular reactivity was diminished in HFpEF versus controls. LA microvascular density tended to be lower in HFpEF and inversely correlated with &bgr;LA. Conclusions—In early-stage hypertensive HFpEF, LA cardiomyocyte hypertrophy, titin hyperphosphorylation, and microvascular dysfunction occur in association with increased systolic and diastolic LA chamber stiffness, impaired atrioventricular coupling, and decreased left ventricular stroke volume. These data indicate that maladaptive LA remodeling occurs early during HFpEF development, supporting a concept of global myocardial remodeling.

Urinary C-type natriuretic peptide: An emerging biomarker for heart failure and renal remodeling

The public health and economic burden of heart failure (HF) is staggering and the need for relevant pathophysiologic and clinical biomarkers to advance the field and improve HF therapy remains high. Renal dysfunction is common among HF patients and is associated with increased HF hospitalization and mortality. It is widely recognized that mechanisms contributing to HF pathogenesis include a complex bidirectional interaction between the kidney and heart, encompassed by the term cardiorenal syndrome (CRS). Among a new wave of urinary biomarkers germane to CRS, C-type natriuretic peptide (CNP) has emerged as an innovative biomarker of renal structural and functional impairment in HF and chronic renal disease states. CNP is a hormone, synthesized in the kidney, and is an important regulator of cell proliferation and organ fibrosis. Hypoxia, cytokines and fibrotic growth factors, which are inherent to both cardiac and renal remodeling processes, are among the recognized stimuli for CNP production and release. In this review we aim to highlight current knowledge regarding the biology and pathophysiological correlates of urinary CNP, and its potential clinical utility as a diagnostic and prognostic biomarker in HF and renal disease states.

Epidemiology of Right Ventricular Dysfunction in Heart Failure with Preserved Ejection Fraction

Despite increasing recognition of the importance of right ventricular (RV) dysfunction (RVD) in the pathophysiology of left heart disease, our understanding of its epidemiology in heart failure (HF) with preserved ejection fraction (HFpEF) remains incomplete. In part, this is due to complex RV geometry and challenging and inconsistent assessment of RV function . Consequently, the prevalence of RVD in HFpEF varies widely depending on study design and population characteristics; however, on average is observed in one third of HFpEF subjects. In these patients, RVD is most commonly associated with an advanced HF state, pulmonary hypertension, atrial fibrillation, right ventricular pacing, and tricuspid valve regurgitation. Whether these associations are causal remains uncertain.Right ventricular dysfunction is recognized to confer poor outcomes in patients with HFpEF, including increased HF hospitalization and higher overall and cardiovascular mortality. Moreover, the prognostic significance of RVD in HFpEF is independent of, and additive to, the severity of pulmonary hypertension. As greater emphasis is placed on phenotyping subgroups of patients with HFpEF in order to tailor therapeutic strategies, improved characterization of the large subset of HFpEF patients with RVD, with and without antecedent pulmonary hypertension may yield critical insights, which inform novel therapeutic interventions.