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1.  Preoperative Assessment of High-Risk Candidates to Predict Survival After Heart Transplantation 
Circulation. Heart failure  2013;6(3):527-534.
Background
Alternate waiting list strategies expand listing criteria for patients awaiting heart transplantation (HTx). We retrospectively analyzed clinical events and outcome of patients listed as high-risk recipients for HTx.
Methods and Results
We analyzed 822 adult patients who underwent HTx of whom 111 patients met high-risk criteria. Clinical data were collected from medical records and outcome factors calculated for 61 characteristics. Significant factors were summarized in a prognostic score. Age >65 years (67%) and amyloidosis (19%) were the most common reasons for alternate listing. High-risk recipients were older (63.2±10.2 versus 51.4±11.8 years; P<0.001), had more renal dysfunction, prior cancer, and smoking. Survival analysis revealed lower post-HTx survival in high-risk recipients (82.2% versus 87.4% at 1-year; 59.8% versus 76.3% at 5-year post-HTx; P=0.0005). Prior cerebral vascular accident, albumin <3.5 mg/dL, re-HTx, renal dysfunction (glomerular filtration rate <40 mL/min), and >2 prior sternotomies were associated with poor survival after HTx. A prognostic risk score (CARRS [CVA, albumin, re-HTx, renal dysfunction, and sternotomies]) derived from these factors stratified survival post-HTx in high-risk (3+ points) versus low-risk (0–2 points) patients (87.9% versus 52.9% at 1-year; 65.9% versus 28.4% at 5-year post-HTx; P<0.001). Low-risk alternate patients had survival comparable with regular patients (87.9% versus 87.0% at 1-year and 65.9% versus 74.5% at 5-year post-HTx; P=0.46).
Conclusions
High-risk patients had reduced survival compared with regular patients post-HTx. Among patients previously accepted for alternate donor listing, application of the CARRS score identifies patients with unacceptably high mortality after HTx and those with a survival similar to regularly listed patients.
doi:10.1161/CIRCHEARTFAILURE.112.000092
PMCID: PMC4283202  PMID: 23505300
heart failure; prognosis; transplantation
2.  Guideline Concordance of Testing for Hyperkalemia and Kidney Dysfunction During Initiation of Mineralocorticoid Receptor Antagonist Therapy in Patients with Heart Failure 
Circulation. Heart failure  2013;7(1):43-50.
Background
Mineralocorticoid receptor antagonists (MRA) reduce morbidity and mortality in heart failure with reduced ejection fraction (HFREF), but can cause hyperkalemia and acute kidney injury. Guidelines recommend measurement of serum potassium (K) and creatinine (Cr) before and serially after MRA initiation, but the extent to which this occurs is unknown.
Methods and Results
Using electronic data from 3 health systems 2005-2008, we performed a retrospective review of laboratory monitoring among 490 patients hospitalized for HFREF who were subsequently initiated on MRA therapy. Median age at time of MRA initiation was 73 years and 37.1% were female. Spironolactone accounted for 99.4% of MRA use. Initial ambulatory MRA dispensing occurred at hospital discharge in 70.0% of cases. In the 30 days before MRA initiation, 94.3% of patients had a K or Cr measurement. Pre-initiation K was >5.0 mmol/L in 1.4% and Cr >2.5 mg/dL in 1.7%. In the 7 days after MRA initiation among patients who remained alive and out of the hospital, 46.5% had no evidence of K measurement; by 30 days, 13.6% remained untested. Patient factors explained a small portion of post-initiation K testing (c-statistic 0.67).
Conclusions
While laboratory monitoring prior to MRA initiation for HFREF is common, laboratory monitoring following MRA initiation frequently does not meet guideline recommendations, even in patients at higher risk for complications. Quality improvement efforts that encourage the use of MRA should also include mechanisms to address recommended monitoring.
doi:10.1161/CIRCHEARTFAILURE.113.000709
PMCID: PMC3924889  PMID: 24281136
heart failure; medication; safety; laboratory testing; mineralocorticoid receptor antagonists; aldosterone
3.  Increased Sarcolipin Expression and Adrenergic Drive in Humans with Preserved Left Ventricular Ejection Fraction and Chronic Isolated Mitral Regurgitation 
Circulation. Heart failure  2013;7(1):194-202.
Background
There is currently no therapy proven to attenuate left ventricular (LV) dilatation and dysfunction in the volume overload induced by isolated mitral regurgitation (MR). To better understand molecular signatures underlying isolated MR, we performed LV gene expression analyses and overlaid regulated genes into Ingenuity Pathway Analysis in patients with isolated MR.
Methods and Results
Gene arrays from LV tissue of 35 patients, taken at the time of surgical repair for isolated MR, were compared to 13 normal controls. Cine-magnetic resonance imaging (MRI) was performed in 31 patients before surgery to measure LV function and volume from serial short axis summation. LV end-diastolic volume was 2-fold (p=0.005) higher than normals and LV ejection fraction (EF) was 64±7% (50-79%) in MR patients. Ingenuity pathway analysis identified significant activation of pathways involved in β-adrenergic, cyclic AMP, and G-protein coupled signaling; while there was downregulation of pathways associated with complement activation and acute phase response. SERCA2a and phospholamban protein were unchanged in MR vs. control LVs. However, mRNA and protein levels of the sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA) regulatory protein sarcolipin, which is predominantly expressed in normal atria, were increased 12- and 6-fold respectively. Immunofluorescence analysis confirmed the absence of sarcolipin in normal LVs and its marked upregulation in MR LVs.
Conclusions
These results demonstrate alterations in multiple pathways associated with β-adrenergic signaling and sarcolipin in the LVs of patients with isolated MR and LVEF > 50%,suggesting a beneficial role for β-adrenergic blockade in isolated MR.
doi:10.1161/CIRCHEARTFAILURE.113.000519
PMCID: PMC3925978  PMID: 24297688
mitral regurgitation; microarray; β-adrenergic signaling; human left ventricle
4.  High Prevalence of Occult Pulmonary Venous Hypertension Revealed by Fluid Challenge in Pulmonary Hypertension 
Circulation. Heart failure  2013;7(1):116-122.
Background
Determining the cause for pulmonary hypertension (PH) is difficult in many patients. Pulmonary arterial hypertension (PAH) is differentiated from pulmonary venous hypertension (PVH) by a wedge pressure (PWP) >15 mmHg in PVH. Patients undergoing RHC for evaluation of PH may be dehydrated and have reduced intravascular volume, potentially leading to a falsely low measurement of PWP and an erroneous diagnosis of PAH. We hypothesized that a fluid challenge during RHC would identify occult pulmonary venous hypertension (OPVH).
Methods and Results
We reviewed the results of patients undergoing fluid challenge in our PH database from 2004-2011. Baseline hemodynamics were obtained and repeated following infusion of 0.5 liters of normal saline over 5-10 minutes. Patients were categorized as OPVH if PWP increased to >15 mm Hg after fluid challenge. Baseline hemodynamics in 207 patients met criteria for PAH. Following fluid challenge, 46 patients (22.2%) developed a PWP >15 mm Hg and were re-classified as OPVH. OPVH patients had a greater increase in PWP compared to PAH patients, p<0.001, and their demographics and comorbid illnesses were similar to PVH patients. There were no adverse events related to fluid challenge.
Conclusions
Fluid challenge at the time of RHC is easily performed, safe, and identifies a large group of patients diagnosed initially with PAH, but for whom OPVH contributes to PH. These results have implications for therapeutic trials in PAH and support the routine use of fluid challenge during RHC in patients with risk factors for PVH.
doi:10.1161/CIRCHEARTFAILURE.113.000468
PMCID: PMC3934572  PMID: 24297689
hemodynamics; pulmonary hypertension; pulmonary heart disease; pulmonary arterial hypertension; fluid challenge
5.  DSAGE Identifies Osteopontin as a Downstream Effector of Integrin-Linked Kinase (ILK) in Cardiac-Specific ILK Knockout Mice 
Circulation. Heart failure  2013;7(1):184-193.
Background
Integrin-linked kinase (ILK) is a serine-threonine kinase that has been linked to human and experimental heart failure, but its role in the heart is not fully understood.
Methods and Results
To define the role of cardiomyocyte ILK, we generated cardiac-specific ILK knockout mice (CSILK-KO) using α-MHC-driven Cre expression. CSILK-KO spontaneously developed lethal dilated cardiomyopathy and heart failure with an early increase in apoptosis, fibrosis, and cardiac inflammation. To identify downstream effectors, we used deep sequence analysis of gene expression (DSAGE) to compare comprehensive transcriptional profiles of CSILK-KO and WT hearts from 10 day old mice before the development of cardiac dysfunction. ~2×106 cDNA clones from each genotype were sequenced, corresponding to 33,274 independent transcripts. 93 genes were altered, using nominal thresholds of >1.4-fold change and p<0.001. The most highly upregulated gene was osteopontin (47-fold increase, p=9.6×10−45), an inflammatory chemokine implicated in heart failure pathophysiology. ILK also regulated osteopontin expression in cardiomyocytes in vitro. Importantly, blocking antibodies to osteopontin mitigated but did not fully rescue the functional decline in CSILK-KO mice.
Conclusions
Cardiomyocyte-specific ILK deletion leads to a lethal cardiomyopathy characterized by cardiomyocyte death, fibrosis, and inflammation. Comprehensive profiling identifies ILK-dependent transcriptional effects and implicates osteopontin as a contributor to these phenotypes.
doi:10.1161/CIRCHEARTFAILURE.113.000649
PMCID: PMC3950354  PMID: 24319095
integrin-linked kinase; dilated cardiomyopathy; osteopontin; transcript profiling
6.  Impact of Atrial Fibrillation on Exercise Capacity in Heart Failure with Preserved Ejection Fraction: A RELAX Trial Ancillary Study 
Circulation. Heart failure  2013;7(1):123-130.
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 remains unclear. RELAX 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 HFpEF patients who were in sinus rhythm (SR) or AF.
Methods and Results
RELAX enrolled 216 HFpEF patients with 79 (37%) in AF, 124 (57%) in SR and 13 in other rhythms. Participants underwent baseline cardiopulmonary exercise testing (CPXT), echocardiogram, biomarker and rhythm status assessment prior to randomization. AF patients were older than those in SR but had similar symptom severity, co-morbidities and renal function. Betablocker use and chronotropic indices were also similar. Despite comparable LV 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 to SR. Pulmonary artery systolic pressure was higher in AF. AF patients had higher NT-proBNP, aldosterone, endothelin-1, troponin I and CITP 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 HFpEF patients with AF is warranted.
doi:10.1161/CIRCHEARTFAILURE.113.000568
PMCID: PMC3972021  PMID: 24162898
atrial fibrillation; heart failure with preserved ejection fraction; exercise capacity
7.  Soluble Tumor Necrosis Factor Receptors and Heart Failure Risk in Older Adults: The Health, Aging, and Body Composition Study 
Circulation. Heart failure  2013;7(1):5-11.
Background
Tumor necrosis factor (TNF) levels are associated with risk for heart failure (HF). The soluble TNF type-1 (sTNF-R1) and type-2 (sTNF-R2) receptors are elevated in patients with manifest HF, but whether they are associated with risk for incident HF is unclear.
Methods and Results
Using Cox proportional hazard models, we examined the association between baseline levels of sTNF-R1 and sTNF-R2 with incident HF risk among 1285 participants of the Health, Aging, and Body Composition Study (age 74.0±2.9 years; 51.4% women; 41.1% black). At baseline, median (interquartile range) of TNF, sTNF-R1, and sTNF R2 levels were 3.14 (2.42-4.06) pg/ml, 1.46 (1.25-1.76) ng/ml, and 3.43 (2.95-4.02) ng/ml, respectively. During a median follow-up of 11.4 (6.9, 11.7) years, 233 (18.1%) participants developed HF. In models controlling for other HF risk factors, TNF (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.02-1.61 per log2 increase), and sTNF-R1 (HR, 1.68; 95%CI, 1.15-2.46 per log2 increase), but not sTNF-R2 (HR, 1.15; 95%CI, 0.80-1.63 per log2 increase), were associated with a higher risk for HF. These associations were consistent across whites and blacks (TNF, sTNF-R1, sTNF-R2, interaction P=0.531, 0.091 and 0.795, respectively), and in both genders (TNF, sTNF-R1, sTNF-R2, interaction P=0.491, 0.672 and 0.999, respectively). TNF-R1 was associated with a higher risk for HF with preserved versus reduced ejection fraction (HR, 1.81; 95%CI, 1.03, 3.18; P=0.038 for preserved vs. HR, 0.90; 95%CI, 0.56, 1.44; P=0.667 for reduced ejection fraction, interaction P=0.05).
Conclusions
In older adults, elevated levels of sTNF-R1 are associated with an increased risk for incident HF. However, addition of TNF-R1 to the previously validated Health ABC HF risk model did not demonstrate material improvement in net discrimination or reclassification.
doi:10.1161/CIRCHEARTFAILURE.113.000344
PMCID: PMC3990649  PMID: 24323631
heart failure; tumor necrosis factor; inflammation
8.  The Scaffold Protein Muscle A-Kinase Anchoring Protein β Orchestrates Cardiac Myocyte Hypertrophic Signaling Required for the Development of Heart Failure 
Circulation. Heart failure  2014;7(4):663-672.
Background
Cardiac myocyte hypertrophy is regulated by an extensive intracellular signal transduction network. In vitro evidence suggests that the scaffold protein muscle A-kinase anchoring protein β (mAKAPβ) serves as a nodal organizer of hypertrophic signaling. However, the relevance of mAKAPβ signalosomes to pathological remodeling and heart failure in vivo remains unknown.
Methods and Results
Using conditional, cardiac myocyte–specific gene deletion, we now demonstrate that mAKAPβ expression in mice is important for the cardiac hypertrophy induced by pressure overload and catecholamine toxicity. mAKAPβ targeting prevented the development of heart failure associated with long-term transverse aortic constriction, conferring a survival benefit. In contrast to 29% of control mice (n=24), only 6% of mAKAPβ knockout mice (n=31) died in the 16 weeks of pressure overload (P=0.02). Accordingly, mAKAPβ knockout inhibited myocardial apoptosis and the development of interstitial fibrosis, left atrial hypertrophy, and pulmonary edema. This improvement in cardiac status correlated with the attenuated activation of signaling pathways coordinated by the mAKAPβ scaffold, including the decreased phosphorylation of protein kinase D1 and histone deacetylase 4 that we reveal to participate in a new mAKAP signaling module. Furthermore, mAKAPβ knockout inhibited pathological gene expression directed by myocyte-enhancer factor-2 and nuclear factor of activated T-cell transcription factors that associate with the scaffold.
Conclusions
mAKAPβ orchestrates signaling that regulates pathological cardiac remodeling in mice. Targeting of the underlying physical architecture of signaling networks, including mAKAPβ signalosome formation, may constitute an effective therapeutic strategy for the prevention and treatment of pathological remodeling and heart failure.
doi:10.1161/CIRCHEARTFAILURE.114.001266
PMCID: PMC4277867  PMID: 24812305
heart failure; hypertrophy; signal transduction
9.  Improved Survival in Heart Transplant Recipients in the United States: Racial Differences in Era Effect 
Circulation. Heart failure  2011;4(2):153-160.
Background
Post-transplant survival in heart transplant recipients has progressively improved during the last 2 decades. It is unknown however whether the major racial groups in the United States have benefited equally.
Methods and Results
We analyzed all primary heart transplant recipients ≥18 years old in the United States during 1987-2008. We compared post-transplant survival in white, black and Hispanic recipients in 5 successive eras (1987-1992, 1993-1996, 1997-2000, 2001-2004, 2005-2008). Early survival was defined as freedom from death or re-transplantation during the first 6-months post-transplant. Longer-term, conditional survival was assessed in patients who survived the first 6 months. There were 29,986 white (81.6%), 4,745 black (12.9%) and 2,017 Hispanic (5.5%) patients in the study cohort. Black patients were at increased risk of early death or re-transplant (hazard ratio [HR] 1.15, 95% confidence interval [CI] 1.05, 1.26) in adjusted analysis. Early post-transplant survival improved (HR 0.83, CI 0.80, 0.87 for successive eras) equally in all three groups (P=0.94 for black-era, 0.40 for Hispanic-era interaction). Longer-term survival improved in white (HR 0.95, CI 0.92, 0.97 for successive eras) but not in black (HR 1.04, 95% CI 0.99, 1.09) or Hispanic (HR 1.02, CI 0.95, 1.09) recipients, resulting in increased disparities in longer-term survival with time.
Conclusions
Early post-transplant survival has improved equally in white, black and Hispanic heart transplant recipients. Longer-term survival has improved in white but not in black or Hispanic recipients resulting in a more marked disparity in outcomes in the current era. These disparities warrant further investigation and targeted interventions.
doi:10.1161/CIRCHEARTFAILURE.110.957829
PMCID: PMC4256951  PMID: 21228316
transplantation; racial disparities; risk factors; outcomes; heart failure
10.  Benefit of Warfarin Compared With Aspirin in Patients With Heart Failure in Sinus Rhythm 
Circulation. Heart failure  2013;6(5):988-997.
Background
The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial found no difference in the primary outcome between warfarin and aspirin in 2305 patients with reduced left ventricular ejection fraction in sinus rhythm. However, it is unknown whether any subgroups benefit from warfarin or aspirin.
Methods and Results
We used a Cox model stepwise selection procedure to identify subgroups that may benefit from warfarin or aspirin on the WARCEF primary outcome. A secondary analysis added major hemorrhage to the outcome. The primary efficacy outcome was time to the first to occur of ischemic stroke, intracerebral hemorrhage, or death. Only age group was a significant treatment effect modifier (P for interaction, 0.003). Younger patients benefited from warfarin over aspirin on the primary outcome (4.81 versus 6.76 events per 100 patient-years: hazard ratio, 0.63; 95% confidence interval, 0.48–0.84; P=0.001). In older patients, therapies did not differ (9.91 versus 9.01 events per 100 patient-years: hazard ratio, 1.09; 95% confidence interval, 0.88–1.35; P=0.44). With major hemorrhage added, in younger patients the event rate remained lower for warfarin than aspirin (5.41 versus 7.25 per 100 patient-years: hazard ratio, 0.68; 95% confidence interval, 0.52–0.89; P=0.005), but in older patients it became significantly higher for warfarin (11.80 versus 9.35 per 100 patient-years: hazard ratio, 1.25; 95% confidence interval, 1.02–1.53; P=0.03).
Conclusions
In patients <60 years, warfarin improved outcomes over aspirin with or without inclusion of major hemorrhage. In patients ≥60 years, there was no treatment difference, but the aspirin group had significantly better outcomes when major hemorrhage was included.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00041938.
doi:10.1161/CIRCHEARTFAILURE.113.000372
PMCID: PMC4242511  PMID: 23881846
aspirin; heart failure; sinus rhythm; stroke; warfarin
11.  Development of Left Ventricular Diastolic Dysfunction with Preservation of Ejection Fraction during Progression of Infant Right Ventricular Hypertrophy 
Circulation. Heart failure  2009;2(6):599-607.
Background
Progressive left ventricular (LV) dysfunction can be a major late complication in patients with chronic right ventricular (RV) pressure overload (e.g., tetralogy of Fallot). We therefore examined LV function (serial echocardiography and ex vivo Langendorff) and histology in a model of infant pressure-load RV hypertrophy (RVH).
Methods and Results
Ten-day-old rabbits (N=6 per time point, total = 48) that underwent pulmonary artery banding (PAB) were sacrificed at 2–8 weeks after PAB, and comparisons were made with age-matched sham controls. LV performance (myocardial performance index, MPI) decreased during the progression of RVH although the LV ejection fraction (EF) was maintained. In addition, RVH caused significant septal displacement, reduced septal contractility, and decreased LV end-systolic (LVDs) and diastolic (LVDd) dimensions, resulting in LV diastolic dysfunction with the appearance of preserved EF. Significant septal and LV free wall apoptosis (myocyte-specific TUNEL and activated caspase-3), fibrosis (Masson’s trichrome stain), and reduced capillary density (CD31 immunostaining) occurred in the PAB group after 6–8 wks (all p<0.05).
Conclusion
This is the first study showing that pressure overload of the RV resulting in RVH causes LV diastolic dysfunction while preserving EF through mechanical and molecular effects upon the septum and LV myocardium. In particular, the development of RVH is associated with septal and LV apoptosis and reduced LV capillary density.
doi:10.1161/CIRCHEARTFAILURE.109.862664
PMCID: PMC4235516  PMID: 19919985
right ventricular hypertrophy; heart failure with preserved ejection fraction; diastolic dysfunction
12.  Practice-level Variation in Use of Recommended Medications Among Outpatients With Heart Failure: Insights From the NCDR PINNACLE Program 
Circulation. Heart failure  2013;6(6):1132-1138.
Background
The objective of this study is to examine practice-level variation in rates of guideline-recommended treatment for outpatients with heart failure and reduced ejection fraction (HFREF), and to examine the association between treatment variation and practice site, independent of patient factors.
Methods and Results
Cardiology practices participating in the NCDR PINNACLE registry from July 2008 – December 2010 were evaluated. Practice rates of treatment with angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) and beta blockers (BB) and an optimal combined treatment measure were determined for patients with HFREF and no documented contraindications. Multivariable hierarchical regression models were adjusted for demographics, insurance status and comorbidities. A median rate ratio (MRR) was calculated for each therapy, which describes the likelihood that the treatment of a patient with given comorbidities would differ at two randomly selected practices. We identified 12,556 patients from 45 practices. The unadjusted practice-level prescription rates ranged from 44% to 100% for ACEI/ARB (median 85%; interquartile range [IQR] 75%–89%), from 49%–100% for BB (median of 92%; IQR 83%–95%) and from 37%–100% for optimal combined treatment (median of 79%; IQR 66%–85%). The adjusted MRR was 1.11 (95% confidence interval [CI] 1.08–1.18) for ACEI/ARB therapy, 1.08 (95% CI 1.05–1.15) for BB therapy and 1.17 (1.13–1.26) for optimal combined treatment.
Conclusions
Variation in the use of guideline-recommended medications for patients with HFREF exists in the outpatient setting. Addressing practice-level differences may be an important component of improving quality of care for patients with HFREF.
doi:10.1161/CIRCHEARTFAILURE.113.000163
PMCID: PMC3894058  PMID: 24130004
heart failure; registry; drugs
13.  Low-Sodium DASH Diet Improves Diastolic Function and Ventricular-Arterial Coupling in Hypertensive Heart Failure with Preserved Ejection Fraction 
Circulation. Heart failure  2013;6(6):1165-1171.
Background
Heart failure with preserved ejection fraction (HFPEF) involves failure of cardiovascular reserve in multiple domains. In HFPEF animal models, dietary sodium restriction improves ventricular and vascular stiffness and function. We hypothesized that the sodium-restricted Dietary Approaches to Stop Hypertension diet (DASH/SRD) would improve left ventricular diastolic function, arterial elastance, and ventricular-arterial (V-A) coupling in hypertensive HFPEF.
Methods and Results
Thirteen patients with treated hypertension and compensated HFPEF consumed the DASH/SRD (target sodium 50 mmol/2100 kcal) for 21 days. We measured baseline and post-DASH/SRD brachial and central BP (via radial arterial tonometry), and cardiovascular function with echocardiographic measures (all previously invasively validated). Diastolic function was quantified via the Parametrized Diastolic Filling formalism, which yields relaxation/viscoelastic (c) and passive/stiffness (k) constants through analysis of Doppler mitral inflow velocity (E-wave) contours. Effective arterial elastance (Ea) end-systolic elastance (Ees), and V-A coupling (defined as the ratio Ees:Ea) were determined using previously published techniques. Wilcoxon matched-pairs tests were used for pre-post comparisons.
The DASH/SRD reduced clinic and 24-hour brachial systolic pressure (155±35 to 138±30 and 130±16 to 123±18 mmHg, both p=.02) and central end-systolic pressure trended lower (116±18 to 111±16 mmHg, p=.12). In conjunction, diastolic function improved (c, 24.3±5.3 to 22.7±8.1 s−1;p=.03; k, 252±115 to 170±37 s−1;p=.03), Ea decreased (2.0±0.4 to 1.7±0.4 mmHg/ml;p=.007), and V-A coupling improved (Ees:Ea, 1.5±0.3 to 1.7±0.4;p=.04).
Conclusions
In hypertensive HFPEF patients, the sodium-restricted DASH diet was associated with favorable changes in ventricular diastolic function, arterial elastance, and V-A coupling.
doi:10.1161/CIRCHEARTFAILURE.113.000481
PMCID: PMC4017662  PMID: 23985432
diastolic heart failure; salt sensitivity hypertension; diet; ventricular/vascular coupling hemodynamics; preserved left ventricular function
14.  Nitroxyl (HNO) a Novel Approach for the Acute Treatment of Heart Failure 
Circulation. Heart failure  2013;6(6):1250-1258.
Background
The nitroxyl (HNO) donor, Angeli’s salt (AS), exerts positive inotropic, lusitropic, and vasodilator effects in vivo that are cyclic AMP-independent. Its clinical utility is limited by chemical instability and co-generation of nitrite that itself has vascular effects. Here we report on effects of a novel, stable, pure HNO donor (CXl-1020) in isolated myoctyes, and intact hearts in experimental models and in patients with heart failure (HF).
Methods and Results
CXL-1020 converts solely to HNO and inactive CXL-1051 with a t1/2 of 2 minutes. In adult mouse ventricular-myocytes, it dose-dependently increased sarcomere shortening by 75–210% (50–500 µM), with a ~30% rise in the peak Ca2+ transient only at higher doses. Neither protein-kinase-A or soluble guanylate-cyclase inhibition altered this contractile response. Unlike isoproterenol, CXL-1020 was equally effective in myocytes from normal or failing hearts. In anesthetized dogs with coronary microembolization-induced HF, CXL-1020 reduced LV end-diastolic pressure and myocardial oxygen-consumption while increasing ejection fraction from 27 to 40% and maximal ventricular power index by 42% (both p<0.05). In conscious dogs with tachypacing-induced HF, CXL-1020 increased contractility assessed by end-systolic elastance, and provided veno-arterial dilation. Heart rate was minimally altered. In patients with systolic HF, CXL-1020 reduced both left and right heart filling pressures and systemic vascular resistance, while increasing cardiac and stroke volume index. Heart rate was unchanged, and arterial pressure declined modestly.
Conclusions
These data show the functional efficacy of a novel pure HNO donor to enhance myocardial function, and show first-in-man evidence for potential utility in heart failure.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01096043, NCT01092325.
doi:10.1161/CIRCHEARTFAILURE.113.000632
PMCID: PMC4110196  PMID: 24107588
nitroxyl; cardiomyopathy; contractility; myocyte; pharmacology; human; canine
15.  Protein Kinase G I and Heart Failure 
Circulation. Heart failure  2013;6(6):1268-1283.
doi:10.1161/CIRCHEARTFAILURE.113.000575
PMCID: PMC4213067  PMID: 24255056
congestive heart failure; cardiac remodeling; ventricular; cyclic GMP-dependent protein kinase
16.  Soluble ST2 in Ambulatory Patients with Heart Failure: Association with Functional Capacity and Long-Term Outcomes 
Circulation. Heart failure  2013;6(6):1172-1179.
Background
ST2 is involved in cardioprotective signaling in the myocardium and has been identified as a potentially promising biomarker in HF. We evaluated ST2 levels and their association with functional capacity and long-term clinical outcomes in a cohort of ambulatory heart failure (HF) patients enrolled in the HF-ACTION study—a multicenter, randomized study of exercise training in HF.
Methods and Results
HF-ACTION randomized 2331 patients with left ventricular ejection fraction <0.35 and New York Heart Association class II–IV HF to either exercise training or usual care. ST2 was analyzed in a subset of 910 patients with evaluable plasma samples. Correlations and Cox models were used to assess the relationship among ST2, functional capacity, and long-term outcomes.
The median baseline ST2 level was 23.7 ng/mL (interquartile range, 18.6–31.8). ST2 was modestly associated with measures of functional capacity. In univariable analysis, ST2 was significantly associated with death or hospitalization (hazard ratio [HR], 1.48; p<0.0001), cardiovascular death or HF hospitalization (HR, 2.14; p<0.0001), and all-cause mortality (HR, 2.33; p<0.0001)(all HRs for log-base2 ng/mL). In multivariable models, ST2 remained independently associated with outcomes after adjustment for clinical variables and amino-terminal pro–B-type natriuretic peptide. However, ST2 did not add significantly to reclassification of risk as assessed by changes in the C statistic, net reclassification improvement, and integrated discrimination improvement.
Conclusions
ST2 was modestly associated with functional capacity and was significantly associated with outcomes in a well-treated cohort of ambulatory HF patients, although it did not significantly affect reclassification of risk.
doi:10.1161/CIRCHEARTFAILURE.113.000207
PMCID: PMC4188425  PMID: 24103327
heart failure; biomarker; prognosis
17.  Longitudinal Changes in Left Ventricular Stiffness: A Community-Based Study 
Circulation. Heart failure  2013;6(5):10.1161/CIRCHEARTFAILURE.113.000383.
Background
Cross sectional studies suggest that left ventricular (LV) and arterial elastance (stiffness) increase with age, but data examining longitudinal changes within human subjects are lacking. Additionally it remains unknown whether age-related LV stiffening is merely a reaction to arterial stiffening or caused by other processes.
Methods and Results
Comprehensive echo-Doppler cardiography was performed in 1402 subjects participating in a randomly-selected community-based study at two examinations separated by 4 years. From this population, 788 subjects had adequate paired data to determine LV end-systolic elastance (Ees), end-diastolic elastance (Eed) and effective arterial elastance (Ea). Over 4 years, blood pressure, Ea and LV mass decreased, coupled with significantly greater use of antihypertensive medications. However, despite reductions in arterial load, Ees increased by 14% (2.10±0.67 to 2.26±0.70 mmHg/ml, p<0.0001) and Eed increased by 8% (0.13±0.03 to 0.14±0.04 mmHg/ml, p<0.0001). Increases in Eed were greater in women than men, whereas Ees changes were similar. Age-related increases in Ees and Eed were correlated with changes in body weight, but were similar in subjects with or without cardiovascular disease. Changes in Ees were correlated with Eed (r=0.5, p<0.0001), but not with other measures of contractility, indicating that the increase in Ees was reflective of passive stiffening rather than enhanced systolic function.
Conclusions
Despite reductions in arterial load with medical therapy, LV systolic and diastolic stiffness increase over time in humans, particularly in women. In addition to blood pressure control, therapies targeting load-independent ventricular stiffening may be effective to treat and prevent age-associated cardiovascular diseases such as heart failure.
doi:10.1161/CIRCHEARTFAILURE.113.000383
PMCID: PMC3807873  PMID: 23811963
aging; stiffness; ventricular function; ventricular/vascular coupling hemodynamics; heart failure
18.  Right Ventricular Dysfunction in Systemic Sclerosis Associated Pulmonary Arterial Hypertension 
Circulation. Heart failure  2013;6(5):10.1161/CIRCHEARTFAILURE.112.000008.
Background
Systemic sclerosis associated pulmonary artery hypertension (SScPAH) has a worse prognosis compared to idiopathic pulmonary arterial hypertension (IPAH), with a median survival of 3 years after diagnosis often due to right ventricular (RV) failure. We tested if SScPAH or systemic sclerosis related pulmonary hypertension with interstitial lung disease (SSc-ILD-PH) imposes a greater pulmonary vascular load than IPAH and/or leads to worse RV contractile function.
Methods and Results
We analyzed pulmonary artery pressures and mean flow in 282 patients with pulmonary hypertension (166 SScPAH, 49 SSc-ILD-PH, 67 IPAH). An inverse relation between pulmonary resistance (RPA) and compliance (CPA) was similar for all three groups, with a near constant resistance × compliance product. RV pressure-volume loops were measured in a subset, IPAH (n=5) and SScPAH (n=7) as well as SSc without PH (SSc-no-PH, n=7) to derive contractile indexes (end-systolic elastance [Ees] and preload recruitable stroke work [Msw]), measures of right ventricular load (arterial elastance [Ea]), and RV-pulmonary artery coupling (Ees/Ea). RV afterload was similar in SScPAH and IPAH (RPA=7.0±4.5 vs. 7.9±4.3 Wood units; Ea=0.9±0.4 vs. 1.2±0.5 mmHg/mL; CPA=2.4±1.5 vs. 1.7±1.1 mL/mmHg; p>0.3 for each). Though SScPAH did not have greater vascular stiffening compared to IPAH, RV contractility was more depressed (Ees=0.8±0.3 vs. 2.3±1.1, p<0.01; Msw=21±11 vs. 45±16, p=0.01), with differential RV-PA uncoupling (Ees/Ea=1.0±0.5 vs. 2.1±1.0, p=.03). This ratio was higher in SSc-no-PH (Ees/Ea = 2.3±1.2, p=0.02 vs. SScPAH).
Conclusions
RV dysfunction is worse in SScPAH compared to IPAH at similar afterload, and may be due to intrinsic systolic function rather than enhanced pulmonary vascular resistive and/or pulsatile loading.
doi:10.1161/CIRCHEARTFAILURE.112.000008
PMCID: PMC3815697  PMID: 23797369
Right ventricular failure; right ventricle-pulmonary arterial coupling; pulmonary hypertension; pressure-volume relationship; systemic sclerosis
19.  Hydrogen Sulfide Attenuates Cardiac Dysfunction Following Heart Failure via Induction of Angiogenesis 
Circulation. Heart failure  2013;6(5):10.1161/CIRCHEARTFAILURE.113.000299.
Background
Hydrogen sulfide (H2S) has been shown to induce angiogenesis in in vitro models and to promote vessel growth in the setting of hind-limb ischemia. The goal of the present study was to determine the therapeutic potential of a stable, long-acting H2S donor, diallyl trisulfide (DATS), in a model of pressure-overload heart failure and to assess the effects of chronic H2S therapy on myocardial vascular density and angiogenesis.
Methods and Results
Transverse aortic constriction (TAC) was performed in mice (C57BL/6J, 8-10 weeks of age). Mice received either vehicle or DATS (200 μg/kg) starting 24 hours after TAC and were followed for 12 weeks using echocardiography. H2S therapy with DATS improved left ventricular remodeling and preserved LV function in the setting of TAC. H2S therapy also increased the expression of the pro-angiogenic factor, vascular endothelial cell growth factor, while decreasing the angiogenesis inhibitor, angiostatin. Further studies revealed that H2S therapy increased the expression of the proliferation marker, Ki67, as well as increased the phosphorylation of endothelial nitric oxide synthase and increased the bioavailability of nitric oxide. Importantly, these changes were associated with an increase in vascular density within the H2S-treated hearts.
Conclusions
These results suggest that H2S therapy attenuates LV remodeling and dysfunction in the setting of heart failure by creating a pro-angiogenic environment for the growth of new vessels.
doi:10.1161/CIRCHEARTFAILURE.113.000299
PMCID: PMC3819451  PMID: 23811964
H2S donor; endothelial nitric oxide synthase; nitric oxide; angiogenesis; diallyl trisulfide
20.  The COP9 Signalosome Is Required for Autophagy, Proteasome-Mediated Proteolysis, and Cardiomyocyte Survival in Adult Mice 
Circulation. Heart failure  2013;6(5):10.1161/CIRCHEARTFAILURE.113.000338.
Background
The COP9 signalosome (CSN) is an evolutionarily conserved protein complex composed of 8 unique protein subunits (CSN1 through CSN8). We have recently discovered in perinatal mouse hearts that CSN regulates not only proteasome-mediated proteolysis but also macroautophagy. However, the physiological significance of CSN in a pots-mitotic organ of adult vertebrates has not been determined. We sought to study the physiological role of CSN8/CSN in adult mouse hearts.
Methods and Results
Csn8 was conditionally ablated in the cardiomyocytes of adult mice (CSN8CKO) using a temporally controlled Cre-LoxP system. Loss of CSN8 accumulated the neddylated forms of cullins and non-cullin proteins, increased ubiquitinated proteins, and stabilized a surrogate substrate of the proteasome in the heart. Autophagic flux was significantly decreased while autophagosomes were markedly increased in CSN8CKO hearts, indicative of impaired autophagosome removal. Furthermore, we observed increased oxidized proteins, massive necrotic cardiomyocytes, and morphological and functional changes characteristic of dilated cardiomyopathy in CSN8CKO mice.
Conclusions
CSN deneddylates substrates more than cullins and is indispensable to cardiomyocyte survival in not only perinatal hearts but also adult hearts. CSN8/CSN regulates both proteasome-mediated proteolysis and the autophagic-lysosomal pathway, critical to the removal of oxidized proteins in the heart.
doi:10.1161/CIRCHEARTFAILURE.113.000338
PMCID: PMC3835345  PMID: 23873473
COP9 signalosome; autophagy; proteasome; NEDD8; heart
21.  Timing and Duration of Interventions in Clinical Trials for Hospitalized Heart Failure Patients 
Circulation. Heart failure  2013;6(5):10.1161/CIRCHEARTFAILURE.113.000518.
doi:10.1161/CIRCHEARTFAILURE.113.000518
PMCID: PMC3845809  PMID: 24046476
heart failure; clinical trial; prognosis; hospitalization
22.  Global Proteomics and Pathway Analysis of Pressure-overload Induced Heart Failure and Its Attenuation by Mitochondrial Targeted Peptides 
Circulation. Heart failure  2013;6(5):10.1161/CIRCHEARTFAILURE.113.000406.
Background
We investigated the protective effects of mitochondrial-targeted antioxidant and protective peptides, SS31 and SS20, on cardiac function, proteomic remodeling and signaling pathways.
Methods and Results
We applied an improved label-free shotgun proteomics approach to evaluate the global proteomics changes in transverse aortic constriction (TAC) induced heart failure, and the associated signaling pathway changes using Ingenuity Pathway Analysis (IPA). We found 538 proteins significantly changed after TAC, which mapped to 53 pathways. The top pathways were in the categories of actin cytoskeleton, mitochondrial function, intermediate metabolism, glycolysis / gluconeogenesis and citrate cycle. Concomitant treatment with SS31 ameliorated the congestive heart failure phenotypes and mitochondrial damage induced by TAC, in parallel with global attenuation of mitochondrial proteome changes, with an average of 84% protection of mitochondrial and 69% of non-mitochondrial protein changes. This included significant amelioration of All the IPA pathways noted above. SS20 had only modest effects on heart failure and this tracked with only partial attenuation of global proteomics changes; furthermore, while actin cytoskeleton pathways were significantly protected in SS20, mitochondrial and metabolic pathways essentially were not.
Conclusions
This study elucidates the signaling pathways significantly changed in pressure-overload induced heart failure. The global attenuation of TAC-induced proteomic alterations by the mitochondrial targeted peptide SS-31 suggests that perturbed mitochondrial function may be an upstream signal to many of pathway alterations in TAC and supports the potential clinical application of mitochondrial-targeted peptide drugs for the treatment heart failure.
doi:10.1161/CIRCHEARTFAILURE.113.000406
PMCID: PMC3856238  PMID: 23935006
heart failure; mitochondria; proteomics; signal transduction
24.  Plasma Free Fatty Acids and Risk of Heart Failure: The Cardiovascular Health Study 
Circulation. Heart failure  2013;6(5):10.1161/CIRCHEARTFAILURE.113.000521.
Background
Although plasma free fatty acid (FFA) concentrations have been associated with lipotoxicity, apoptosis, and risk of diabetes and coronary heart disease, it is unclear whether FFA levels are associated with heart failure (HF).
Methods and Results
To test the hypothesis that plasma concentration of FFA is positively associated with incident HF, we prospectively analyzed data on 4248 men and women free of HF at baseline and aged 65+ years from the Cardiovascular Health Study. FFA concentration was measured in duplicate by the Wako enzymatic method. Incident HF was validated by a centralized Events Committee. We used Cox proportional hazards to estimate the hazard ratio of HF per standard deviation (SD) of FFA. During a median follow up of 10.5 y, 1,286 new cases of HF occurred. In a multivariable model adjusting for clinic site, comorbidity, demographic, anthropometric, and lifestyle factors, each SD (0.2 mEq/L) higher plasma FFA was associated with 12% (95% CI: 6% to 19%) higher risk of HF. Controlling for time-varying diabetes and coronary heart disease did not change the results [HR per SD: 1.16 (95% CI: 1.09–1.23)].
Conclusions
A single measure of plasma FFA obtained later in life is associated with a higher risk of HF in older adults. Additional studies are needed to explore biologic mechanisms by which FFA may influence the risk of HF and determine whether FFA could serve as a novel pharmacological target for HF prevention.
doi:10.1161/CIRCHEARTFAILURE.113.000521
PMCID: PMC3884584  PMID: 23926204
heart failure; epidemiology; nutrition; free fatty acids
25.  The Clinical Profile and Under-Diagnosis of Pulmonary Hypertension in U.S. Veteran Patients 
Circulation. Heart failure  2013;6(5):906-912.
Background
Pulmonary hypertension (PH) is a key contributor to cardiovascular morbidity and early mortality; however, reports are lacking on the epidemiology of PH in at-risk patient populations.
Methods and Results
The echocardiography registries from two major Veterans Affairs hospitals were accessed to identify patients with at least moderate PH, defined here as a pulmonary artery systolic pressure (PASP) ≥60 mmHg detected echocardiographically. From a total of 10,471 individual patient transthoracic echocardiograms, we identified moderate or severe PH in 340 patients (332 men; mean 77 y, mean PASP 69.4 ± 10.5 mmHg), of which PH was listed as a diagnosis in the medical record for only 59 (17.3%). At a mean of 832 days (0-4817 d) following echocardiography diagnosing PH, 150 (44.1%) patients were deceased. Pulmonary hypertension was present without substantial left heart remodeling: the mean left ventricular (LV) ejection fraction was 0.50 ± 0.16, LV end-diastolic dimension was 4.9 ± 1.0 cm, and left atrial dimension was 4.4 ± 0.7 cm. Cardiac catheterization (n=122, 36%) demonstrated a mean pulmonary artery pressure of 40.5 ± 11.4 mmHg, pulmonary capillary wedge pressure of 22.6 ± 8.9 mmHg, and pulmonary vascular resistance of 4.6 ± 2.9 Wood units. Diagnostic strategies for PH were variable and often incomplete; for example, only 16% of appropriate patients were assessed with a nuclear ventilation/perfusion (V/Q) scan for thromboembolic causes of PH.
Conclusions
In an at-risk patient population, PH is under-diagnosed and associated with substantial mortality. Enhanced awareness is necessary among practitioners regarding contemporary PH diagnostic strategies.
doi:10.1161/CIRCHEARTFAILURE.112.000091
PMCID: PMC3894604  PMID: 23811965
pulmonary hypertension; diagnostic method; population

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