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1.  Sympathoexcitation in Rats With Chronic Heart Failure Depends on Homeobox D10 and MicroRNA-7b Inhibiting GABBR1 Translation in Paraventricular Nucleus 
Circulation. Heart failure  2015;9(1):e002261.
Background
Chronic heart failure (CHF) increases sympathoexcitation through Angiotensin II (ANG II) receptors (AT1R) in the paraventricular nucleus (PVN). Recent publications indicate down regulation of γ-aminobutyric acid B-type receptor 1 (GABBR1) and has a binding site for microRNA-7b (miR-7b) that is expressed in the PVN. We hypothesized that ANG II regulates sympathoexcitation through homeobox D10 (HoxD10), which regulates miR-7b in other tissues.
Methods and Results
Ligation of the left anterior descendent coronary artery in rats caused CHF and sympathoexcitation. PVN expression of AT1R, HoxD10 and miR-7b was increased, while GABBR1 was lower in CHF. Infusion of miR-7b in the PVN caused sympathoexcitation in control animals, and enhanced the changes in CHF. Antisense miR-7b infused in PVN normalized GABBR1 expression while attenuating CHF symptoms including sympathoexcitation. A luciferase reporter assay detected miR-7b binding to the 3’-UTR of GABBR1 that was absent after targeted mutagenesis. ANG II induced HoxD10 and miR-7b in NG108 cells, effects blocked by AT1R-blocker losartan (Los) and by HoxD10 silencing. miR-7b transfection into NG108 cells decreased GABBR1 expression, which was inhibited by miR-7b antisense. In vivo PVN knockdown of AT1R attenuated the symptoms of CHF, while HoxD10 overexpression exaggerated them. Finally, in vivo PVN ANG II infusion caused dose dependent sympathoexcitation that was abrogated by miR-7b antisense and exaggerated by GABBR1 silencing.
Conclusions
There is an ANG II/AT1R/HoxD10/miR-7b/GABBR1 pathway in the PVN that contributes to sympathoexcitation and deterioration of cardiac function in CHF.
doi:10.1161/CIRCHEARTFAILURE.115.002261
PMCID: PMC4692171  PMID: 26699387
γ-aminobutyric acid; miR-7b; HoxD10; PVN, ANG II
2.  Psychosocial Factors and Risk of Incident Heart Failure: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Circulation. Heart failure  2015;9(1):e002243.
Background
Heart failure is a major source of morbidity and mortality in the United States. Psychosocial factors have frequently been studied as risk factors for coronary heart disease, but not for heart failure.
Methods and Results
We examined the relationship between psychological status and incident heart failure among 6,782 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA). Anger, anxiety, chronic stress, depressive symptoms, and hostility were measured using validated scales and physician reviewers adjudicated incident heart failure events. Cox proportional hazards models were used to adjust for relevant demographic, behavioral, and physiological covariates. Interactions by age, race, sex, and self-reported health were examined in exploratory analyses. During a mean follow up of 9.3 years, 242 participants developed incident heart failure. There was no association between psychosocial factors and heart failure hazard ratios (95% CI) for highest vs. lowest quartile: anger=1.14 (0.81-1.60), anxiety=0.74 (0.51-1.07), chronic stress=1.25 (0.90-1.72), depressive symptoms=1.19 (0.76-1.85), and hostility=0.95 (0.62-1.42). In exploratory analysis, among the participants reporting fair/poor health at baseline, those reporting high vs. low levels of anxiety, chronic stress, and depressive symptoms had 2-fold higher risk of incident heart failure, but there was no association for those with good/very good/excellent self-reported health.
Conclusions
Overall these psychosocial factors were not significantly associated with incident heart failure. However, for participants reporting poor health at baseline, there was evidence that anxiety, chronic stress, and depressive symptoms were associated with increased risk of heart failure. Future research with greater statistical power is necessary to replicate these findings and seek explanations.
doi:10.1161/CIRCHEARTFAILURE.115.002243
PMCID: PMC4692172  PMID: 26699386
epidemiology; heart failure; anxiety; depression; stress
3.  Elevated Soluble Fms-Like Tyrosine Kinase 1 and Placental-Like Growth Factor Levels Are Associated With Development and Mortality Risk in Heart Failure 
Circulation. Heart failure  2015;9(1):e002115.
Background
Vascular-endothelial dysfunction may play an important role in the progression of heart failure. We hypothesize that elevated levels of vascular markers, placental growth factor (PlGF) and soluble Fms like tyrosine kinase-1 (sFlt-1) are associated with adverse outcomes in patients with heart failure (HF). We also assessed possible triggers of sFlt-1 elevation in animal HF models.
Methods and Results
We measured plasma PlGF and sFlt-1 in 791 HF patients undergoing elective coronary angiogram. Median (IQR) PlGF and sFlt-1 levels were 24 (20–29) pg/ml and 382 (277–953) pg/ml, respectively. After five years of follow up, and after using receiver operator characteristic curves to determine optimal cutoffs, high levels of sFlt-1 (≥ 280 pg/ml; adjusted hazard ratio (HR) = 1.47, 95% confidence interval (CI) 1.03–2.09, p=0.035) but not PlGF (≥25 pg/ml; adjusted HR = 1.26, 95%CI 0.94–1.71, p=0.12) were associated with adverse cardiovascular outcomes. In addition, significant elevation of sFlt-1 levels was observed in left anterior descending artery ligation and transverse aortic constriction HF mouse models after 4 and 8 weeks of follow up, suggesting vascular stress and ischemia as triggers for sFlt-1 elevation in HF.
Conclusions
Circulating sFlt-1 is generated as a result of myocardial injury and subsequent HF development. Elevated levels of sFlt-1 are associated with adverse outcomes in stable patients with HF.
doi:10.1161/CIRCHEARTFAILURE.115.002115
PMCID: PMC4692173  PMID: 26699385
heart failure; vascular markers; placental-like growth factor; soluble Fms-like tyrosine kinase 1 receptor
4.  Cardiovascular Health Status and Incidence of Heart Failure in the Framingham Offspring Study 
Circulation. Heart failure  2015;9(1):e002416.
Background
The American Heart Association Cardiovascular Health (CVH) score is inversely associated with cardiovascular disease, but its relations to cardiac remodeling traits and to heart failure (HF) incidence have not been examined.
Methods and Results
A 14-point score was constructed for each participant based on the presence of poor, intermediate or ideal status on each of the 7 CVH metrics (ideal score=14). We related the CVH score to echocardiographic traits cross-sectionally, and to HF incidence prospectively in the Framingham Offspring Study. In age- and sex-adjusted models, a higher CVH score was associated with lower left ventricular (LV) mass, LV wall thickness, LV diastolic dimension, and left atrial dimension (p<0.01 for all; N=2392, mean age 58 years, 56% women), and with a 12-15% lower odds of prevalent LV concentric remodeling and concentric hypertrophy, respectively (p<0.0001 for both). On follow-up (mean 12.3 years), 188 incident HF events were observed in 3201 participants (mean age 59 years, 53% women). In age- and sex-adjusted Cox proportional hazards models, the CVH score was inversely associated with HF incidence (hazards ratio [HR] per 1-point higher CVH score 0.77, 95% CI 0.72-0.83). This association was partially attenuated upon adjustment for LV mass and interim myocardial infarction (HR 0.84, 95% CI 0.76-0.93) and was consistent for HF with preserved and reduced ejection fractions.
Conclusions
In our community-based sample, comprised predominantly of middle-aged white individuals of European descent, better CVH was associated with lower HF incidence, in part due to a lower prevalence of adverse cardiac remodeling.
doi:10.1161/CIRCHEARTFAILURE.115.002416
PMCID: PMC4692176  PMID: 26699391
American Heart Association; prevention; heart failure; remodeling; lifestyle
5.  Mortality Associated With Heart Failure After Myocardial Infarction: A Contemporary Community Perspective 
Circulation. Heart failure  2015;9(1):e002460.
Background
Contemporary data are lacking on the prognostic importance of heart failure (HF) after myocardial infarction (MI). We evaluated the prognostic impact of HF post MI according to preserved/reduced ejection fraction (EF) and the timing of its occurrence.
Methods and Results
All Olmsted County, Minnesota residents (n=2,596) with incident MI diagnosed in 1990-2010 and no prior HF were followed through March 2013. Cox models were used to examine (1) the hazard ratios (HRs) for death associated with HF type and timing; and (2) secular trends in survival by HF status. During a mean follow-up of 7.6 years, there were 1116 deaths, 634 in the 902 patients who developed HF (70%), and 482 in the 1694 patients who did not develop HF (28%). After adjustment for age and sex, HF as a time-dependent variable was strongly associated with mortality (HR=3.31, 95% confidence interval [CI]: 2.93-3.75), particularly from cardiovascular causes (HR=4.20, 95% CI: 3.50-5.03). Further adjustment for MI severity and comorbidity, acute treatment, and recurrent MI moderately attenuated these associations (HR=2.49 and 2.94 for all-cause and cardiovascular mortality, respectively). Mortality did not differ by EF, but was higher for delayed- vs. early-onset HF (p for heterogeneity=0.002). The age- and sex-adjusted 5-year survival estimates in 2001-2010 vs. 1990-2000 were 82% and 81% among HF-free and 61% and 54% among HF patients, respectively (p for heterogeneity of trends=0.05).
Conclusions
HF markedly increases the risk of death after MI. This excess risk is similar regardless of EF but greater for delayed- vs. early-onset HF. Mortality after MI declined over time, primarily as a result of improved HF survival.
doi:10.1161/CIRCHEARTFAILURE.115.002460
PMCID: PMC4692179  PMID: 26699392
myocardial infarction; heart failure; mortality; ejection fraction; epidemiology; trends; cohort studies; secondary prevention
6.  Prediction of All-Cause Mortality Based on the Direct Measurement of Intrathoracic Impedance 
Circulation. Heart failure  2015;9(1):e002543.
Background
Intrathoracic impedance-derived OptiVol fluid index calculated using implanted devices has been shown to predict mortality; direct measurements of impedance have not been examined. We hypothesized that baseline measured impedance predicts all-cause mortality; changes in measured impedance result in a change in the predicted mortality; and the prognostic value of measured impedance is additive to the calculated OptiVol fluid index.
Methods and Results
A retrospective analysis of 146,238 patients within the Medtronic CareLink data base with implanted devices was performed. Baseline measured impedance was determined using daily values averaged from month 6 to 9 post implant and were used to divide patients into tertiles; Group L= Low Impedance: ≤ 65 ohms, M= Medium Impedance: 66–72 ohms, H= High Impedance: ≥ 73 ohms. Change in measured impedance was determined from values averaged from month 9 to 12 post implant compared to the 6 to 9 month values. OptiVol fluid index was calculated using published methods. All-cause mortality was assessed beginning 9 months post implant; changes in mortality beginning 12 months post implant. Baseline measured impedance predicted all-cause mortality; 5 year mortality for group L was 41%, M was 29%, H was 25%, p < 0.001 among all groups. Changes in measured impedance resulted in a change in the predicted mortality; the prognostic value of measured impedance was additive to the OptiVol fluid index.
Conclusions
Direct measurements of intrathoracic impedance using an implanted device can be used to stratify patients at varying mortality risk.
doi:10.1161/CIRCHEARTFAILURE.115.002543
PMCID: PMC4692195  PMID: 26699393
heart failure; impedance; all-cause mortality
7.  Association of Serum Erythropoietin with Cardiovascular Events, Kidney Function Decline and Mortality: The Health ABC Study 
Circulation. Heart failure  2016;9(1):e002124.
Background
Studies suggest that in patients with heart failure (HF), high serum erythropoietin is associated with risk of recurrent HF and mortality. Trials of erythropoietin stimulating agents in persons with kidney disease have also suggested an increased incidence of adverse clinical events. No studies have evaluated the association of endogenous erythropoietin levels with clinical outcomes in the community living older adults.
Methods and Results
Erythropoietin concentration was measured in 2,488 participants aged 70–79 years in the Health, Aging and Body Composition Study. Associations of erythropoietin with incident HF, coronary heart disease (CHD), stroke, mortality, and ≥30% decline in estimated glomerular filtration rate (eGFR) were examined using Cox proportional hazards and logistic regression over 10.7 years of follow up. Mean (SD) age was 75 (3) years and median (quartile 1, quartile 3) erythropoietin was 12.3 (9.0, 17.2) mIU/mL. There were 503 incident HF events and each doubling of serum erythropoietin was associated with a 25% increased risk of incident HF 1.25 (95% CI 1.13, 1.48) after adjusting for demographics, prevalent cardiovascular disease (CVD), CVD risk factors, kidney function and serum hemoglobin. There was no interaction of serum erythropoietin with chronic kidney disease or anemia (p>0.50). There were 330 incident CHD events, 161 strokes, 1,112 deaths and 698 outcomes of ≥ 30% decline in eGFR. Serum erythropoietin was not significantly associated with these outcomes.
Conclusions
Higher levels of endogenous erythropoietin are associated with incident HF in older adults. Studies need to elucidate the mechanisms through which endogenous erythropoietin levels associate with specific outcomes.
doi:10.1161/CIRCHEARTFAILURE.115.002124
PMCID: PMC4698899  PMID: 26721912
erythropoietin; heart failure; chronic kidney disease; cardiovascular outcomes; death
8.  Heart Failure with Preserved Ejection Fraction Induces Beiging in Adipose Tissue 
Circulation. Heart failure  2016;9(1):e002724.
Background
Despite the increasing prevalence of heart failure with preserved ejection fraction (HFpEF) in humans, there are no evidence-based therapies for HFpEF. Clinical studies suggest a relationship between obesity-associated dysfunctional adipose tissue (AT) and HFpEF. However an apparent obesity paradox exists in some HF populations with a higher BMI. We sought to determine if HFpEF exerted effects on AT and investigated the involved mechanisms.
Methods and Results
Mice underwent d-aldosterone infusion, uninephrectomy, and were given 1% saline for 4 weeks. HFpEF mice developed hypertension, left ventricular hypertrophy, diastolic dysfunction and had higher myocardial natriuretic peptide expression. Although body weights were similar in HFpEF and sham-operated mice, white AT (WAT) was significantly smaller in HFpEF than Sham (epididymal AT: 7.59 vs. 10.67 mg/g; inguinal AT: 6.34 vs. 8.38 mg/g). These changes were associated with smaller adipocyte size and increased beiging markers (ucp-1, cidea and eva) in WAT. Similar findings were seen in HFpEF induced by TAC. Increased activation of natriuretic peptide signaling was seen in WAT of HFpEF mice. The ratio of the signaling receptor, npra, to the clearance receptor, nprc, was increased as was p38 MAPK activation. However, HFpEF mice failed to regulate body temperature during cold temperature exposure. In HFpEF, despite a larger brown AT mass (BAT; 5.96 vs. 4.50 mg/g), BAT showed reduced activity with decreased ucp1, cidea and eva expression, and decreased expression of lipolytic enzymes (hsl, lpl and fabp4) vs. Sham.
Conclusions
These findings show that HFpEF is associated with beiging in WAT and with dysfunctional BAT.
doi:10.1161/CIRCHEARTFAILURE.115.002724
PMCID: PMC4698901  PMID: 26721917
heart failure with preserved ejection fraction; adipose tissue; beiging; natriuretic peptides
9.  Health Literacy Mediates the Relationship between Age and Health Outcomes in Patients with Heart Failure 
Circulation. Heart failure  2016;9(1):e002250.
BACKGROUND
Prior studies have linked frequent rehospitalizations for heart failure (HF) and increased mortality with older age, higher severity of HF, lack of an evidence-based medication regimen, and inadequate health literacy. However, the pathway between age and health outcomes in patients with HF remains unknown. Therefore, the purpose of this study was to test whether the association between age and health outcomes can be explained by severity of HF, evidence-based medication use, and health literacy in patients with HF.
METHODS AND RESULTS
This was a longitudinal study of 575 rural patients with HF recruited from outpatient clinics and hospitals. Demographics, clinical data, and health literacy were collected at baseline. HF readmissions and cardiac mortality were followed for 2 years. 57% of patients were 65 years or older. Older HF patients were more likely to have low health literacy and less likely to be prescribed angiotensin-converting-enzyme inhibitors or beta-blockers. Using Kaplan-Meier survival curves with log-rank tests, health outcomes were significantly worse in patients who were 65 years or older and in those with low health literacy. Separate Cox regressions revealed that age and health literacy predicted worse health outcomes (p =.006 and <.001, respectively). When health literacy was entered into the model, the hazard ratio for age changed from 1.49 to 1.29 (a 41% reduction); age was no longer a significant predictor of health outcomes, but health literacy remained significant (p < .001), demonstrating mediation.
CONCLUSIONS
Health literacy mediates the relationship between age and health outcomes in adults with HF.
CLINICAL TRIAL REGISTRATION
URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00415545.
doi:10.1161/CIRCHEARTFAILURE.115.002250
PMCID: PMC4698978  PMID: 26721913
health literacy; heart failure; health outcomes; aging; mediator
10.  The Importance of Abnormal Chloride Homeostasis in Stable Chronic Heart Failure 
Circulation. Heart failure  2016;9(1):e002453.
Background
The aim of this analysis was to determine the long-term prognostic value of lower serum chloride in patients with stable chronic heart failure.
Electrolyte abnormalities are prevalent in patients with chronic heart failure. Little is known regarding the prognostic implications of lower serum chloride.
Methods and Results
Serum chloride was measured in 1,673 consecutively consented stable patients with a history of heart failure undergoing elective diagnostic coronary angiography. All patients were followed for 5-year all-cause mortality, and survival models were adjusted for variables that confounded the chloride-risk relationship. The average chloride level was 102±4 mEq/L. Over 6,772 person-years of follow-up, there were 547 deaths. Lower chloride (per standard deviation decrease) was associated with a higher adjusted risk of mortality (HR 1.29, 95%CI 1.12–1.49, P<0.001). Chloride levels net-reclassified risk in 10.4% (P=0.03) when added to a multivariable model (with a resultant C-statistic of 0.70), in which sodium levels were not prognostic (P=0.30). In comparison to those with above first quartile chloride (≥101 mEq/L) and sodium (≥138 meq/L), subjects with first quartile chloride had a higher adjusted mortality risk, whether they had first quartile sodium (HR 1.35, 95%CI 1.08–1.69, P=0.008) or higher (HR 1.43, 95%CI 1.12–1.85, P=0.005). However, subjects with first quartile sodium but above first quartile chloride had no association with mortality (P=0.67).
Conclusions
Lower serum chloride levels are independently and incrementally associated with increased mortality risk in patients with chronic heart failure. A better understanding of the biological role of serum chloride is warranted.
doi:10.1161/CIRCHEARTFAILURE.115.002453
PMCID: PMC4702267  PMID: 26721916
heart failure; sodium; chloride; electrolyte imbalances
11.  Cancer Therapy-Related Cardiac Dysfunction and Heart Failure Part 1: Definitions, Pathophysiology, Risk Factors, and Imaging 
Circulation. Heart failure  2016;9(1):e002661.
Advances in cancer therapy have resulted in significant improvement in long-term survival for many types of cancer, but have also resulted in untoward side effects associated with treatment. One such complication that has become increasingly recognized is the development of cardiomyopathy and heart failure. Whether a previously healthy person from a cardiovascular perspective develops cancer therapy related cardiac dysfunction or a high-risk cardiovascular patient requires cancer therapy, the team of oncologists and cardiologists must be better equipped with an evidence-based approach to care for these patients across the spectrum. Although the toxicities associated with various cancer therapies are well recognized, limitations to our understanding of the appropriate course of action remain. In this first of a 2-part review, we discuss the epidemiologic, pathophysiologic, risk factors, and imaging aspects of cancer therapy related cardiac dysfunction and heart failure. In a subsequent second part, we discuss the prevention and treatment aspects, concluding with a section on evidence gap and future directions. We focus on adult patients in all stages of cancer therapy from pre-treatment surveillance, to ongoing therapy, and long-term follow up.
doi:10.1161/CIRCHEARTFAILURE.115.002661
PMCID: PMC4709035  PMID: 26747861
cardiomyopathy; heart failure; treatment; left ventricular ejection fraction; left ventricular dysfunction; chemotherapy; cardiotoxicity; cancer therapy; anthracycline; trastuzumab
12.  Comparative Effectiveness of Implantable Cardioverter Defibrillators for Primary Prevention in Women 
Circulation. Heart failure  2016;9(1):e002630.
Background
Clinical trials of implantable cardioverter defibrillators (ICDs) for primary prevention enrolled a limited number of women. We sought to examine clinical practice data to compare survival rates among women with heart failure (HF) with or without a primary prevention ICD.
Methods and Results
We linked data from 264 US hospitals included in the Get With The Guidelines for Heart Failure (GWTG-HF) registry with data from the Centers for Medicare and Medicaid Services (CMS). From these sources, we propensity score matched 430 women with HF who received a primary prevention ICD to 430 women who did not; we further adjusted using a Cox proportional hazards model. Median follow up was 3.4 and 3.0 years, respectively. For comparison, we matched 859 men receiving an ICD with 859 not; median follow-up was 3.9 vs 2.9 years. In the matched cohorts, an ICD was associated with similarly better survival in women (HR 0.78 95% CI 0.66-0.92 p=0.003) and men (HR 0.76 95% CI 0.67-0.87 p<0.001). There was no interaction between sex and presence of an ICD with respect to survival (p = 0.79).
Conclusions
Among patients with heart failure with reduced LVEF, a primary prevention ICD was associated with a significant survival advantage among women as well as among men. These findings support guideline-directed use of primary prevention ICDs in eligible patients.
doi:10.1161/CIRCHEARTFAILURE.115.002630
PMCID: PMC4712727  PMID: 26758365
comparative effectiveness; heart failure; implantable cardioverter defibrillator; morbidity/mortality; women
13.  Chronic Co-Administration of Sepiapterin and L-Citrulline Ameliorates Diabetic Cardiomyopathy and Myocardial Ischemia/Reperfusion Injury in Obese Type 2 Diabetic Mice 
Circulation. Heart failure  2016;9(1):e002424.
Background
Diabetic heart disease is associated with tetrahydrobiopterin (BH4) oxidation and high arginase activity, leading to endothelial nitric oxide synthase (eNOS) dysfunction. Sepiapterin (SEP) is a BH4 precursor, and L-citrulline (L-Cit) is converted to eNOS substrate, L-arginine. Whether SEP and L-Cit are effective at reducing diabetic heart disease is not known. The present study examined the effects of SEP and L-Cit on diabetic cardiomyopathy and ischemia/reperfusion injury in obese type 2 diabetic mice.
Methods and Results
Db/db and C57BLKS/J mice at 6-8 weeks of age received vehicle, SEP, or L-Cit orally alone or in combination for 8 weeks. Cardiac function was evaluated with echocardiography. Db/db mice displayed hyperglycemia, obesity, and normal blood pressure and cardiac function compared with C57BLKS/J mice at 6-8 weeks of age. After vehicle treatment for 8 weeks, db/db mice had reduced ejection fraction, mitral E/A ratio, endothelium-dependent relaxation of coronary arteries, BH4 concentrations, ratio of eNOS dimers/monomers, and nitric oxide levels compared with vehicle-treated C57BLKS/J mice. These detrimental effects of diabetes were abrogated by co-administration of SEP and L-Cit. Myocardial infarct size was increased, and coronary flow rate and ±dP/dt were decreased during reperfusion in vehicle-treated db/db mice subjected to ischemia/reperfusion injury compared to control mice. Co-administration of SEP and L-Cit decreased infarct size and improved coronary flow rate and cardiac function in both C57BLKS/J and db/db mice.
Conclusions
Co-administration of SEP and L-Cit limits diabetic cardiomyopathy and ischemia/reperfusion injury in db/db mice through a BH4/eNOS/nitric oxide pathway.
doi:10.1161/CIRCHEARTFAILURE.115.002424
PMCID: PMC4714787  PMID: 26763290
tetrahydrobiopterin; nitric oxide synthase; diabetic cardiomyopathy; ischemia reperfusion injury; type 2 diabetes mellitus
14.  Gradual Increases in Scheduled and Actual Early Follow Up after Heart Failure Hospitalization: Two Steps Forward or One Step Forward? 
Circulation. Heart failure  2016;9(1):10.1161/CIRCHEARTFAILURE.115.002856 e002856.
doi:10.1161/CIRCHEARTFAILURE.115.002856
PMCID: PMC4734088  PMID: 26754627
15.  Rapid and Highly Accurate Prediction of Poor Loop Diuretic Natriuretic Response in Patients With Heart Failure 
Circulation. Heart failure  2016;9(1):e002370.
Background
Removal of excess sodium and fluid is a primary therapeutic objective in acute decompensated heart failure (ADHF) and commonly monitored with fluid balance and weight loss. However, these parameters are frequently inaccurate or not collected and require a delay of several hours after diuretic administration before they are available. Accessible tools for rapid and accurate prediction of diuretic response are needed.
Methods and Results
Based on well-established renal physiologic principles an equation was derived to predict net sodium output using a spot urine sample obtained one or two hours following loop diuretic administration. This equation was then prospectively validated in 50 ADHF patients using meticulously obtained timed 6-hour urine collections to quantitate loop diuretic induced cumulative sodium output. Poor natriuretic response was defined as a cumulative sodium output of <50 mmol, a threshold that would result in a positive sodium balance with twice-daily diuretic dosing. Following a median dose of 3 mg (2–4 mg) of intravenous bumetanide, 40% of the population had a poor natriuretic response. The correlation between measured and predicted sodium output was excellent (r=0.91, p<0.0001). Poor natriuretic response could be accurately predicted with the sodium prediction equation (AUC=0.95, 95% CI 0.89–1.0, p<0.0001). Clinically recorded net fluid output had a weaker correlation (r=0.66, p<0.001) and lesser ability to predict poor natriuretic response (AUC=0.76, 95% CI 0.63–0.89, p=0.002).
Conclusions
In patients being treated for ADHF, poor natriuretic response can be predicted soon after diuretic administration with excellent accuracy using a spot urine sample.
doi:10.1161/CIRCHEARTFAILURE.115.002370
PMCID: PMC4741370  PMID: 26721915
diuretics; heart failure; sodium; diuretic resistance; poor natriuretic response
16.  Influence of Titration of Neurohormonal Antagonists and Blood Pressure Reduction on Renal Function and Decongestion in Decompensated Heart Failure 
Circulation. Heart failure  2015;9(1):e002333.
Background
Reduction in systolic blood pressure (SBP reduction) during the treatment of acute decompensated heart failure (ADHF) is strongly and independently associated with worsening renal function (WRF). Our objective was to determine if SBP reduction or titration of oral neurohormonal antagonists during ADHF treatment negatively influences diuresis and decongestion.
Methods and Results
SBP reduction was evaluated from admission to discharge in consecutive ADHF admissions (n=656). Diuresis and decongestion was examined across a range of parameters such as diuretic efficiency, fluid output, hemoconcentration, and diuretic dose. The average reduction in SBP was 14.4 ± 19.4 mmHg and 77.6% of the population had discharge SBP lower than admission. SBP reduction was strongly associated with WRF (OR=1.9, 95% CI: 1.2-2.9, p=0.004), a finding that persisted after adjusting for parameters of diuresis and decongestion (OR=2.0, 95% CI: 1.3-3.2, p=0.002). However, SBP reduction did not negatively impact diuresis or decongestion (p≥0.25 for all parameters). Uptitration of neurohormonal antagonists occurred in over 50% of admissions and was associated with a modest additional reduction in blood pressure (≤ 5.6 mmHg). Notably, WRF was not increased and diuretic efficiency was significantly improved with the uptitration of neurohormonal antagonists.
Conclusions
Despite a higher rate of WRF, blood pressure reduction was not associated with worsening of diuresis or decongestion. Furthermore, titration of oral neurohormonal antagonists was actually associated with improved diuresis in this cohort. These results provide reassurance that the guideline recommended titration of chronic oral medication during ADHF hospitalization may not be antagonistic to the short-term goal of decongestion.
doi:10.1161/CIRCHEARTFAILURE.115.002333
PMCID: PMC4741376  PMID: 26699390
renal function; acute heart failure; diuretics; blood pressure
17.  Choline Diet and Its Gut Microbe Derived Metabolite, Trimethylamine N-Oxide (TMAO), Exacerbate Pressure Overload-Induced Heart Failure 
Circulation. Heart failure  2015;9(1):e002314.
Background
Trimethylamine N-oxide (TMAO), a gut microbe dependent metabolite of dietary choline and other trimethylamine containing nutrients, is both elevated in the circulation of patients suffering from heart failure (HF) and heralds worse overall prognosis. In animal studies, dietary choline or TMAO significantly accelerate atherosclerotic lesion development in ApoE deficient mice, and reduction in TMAO levels inhibits atherosclerosis development in the LDL receptor knockout mouse.
Methods and Results
C57BL6/J mice were fed either a control diet, a diet containing choline (1.2%) or a diet containing TMAO (0.12%) starting 3 weeks prior to surgical TAC. Mice were studied for 12 weeks following TAC. Cardiac function and left ventricular structure were monitored at 3-week intervals using echocardiography. Twelve weeks post-TAC myocardial tissues were collected to evaluate cardiac and vascular fibrosis, and blood samples were evaluated for cardiac BNP, choline, and TMAO levels. Pulmonary edema, cardiac enlargement, and left ventricular ejection fraction (LVEF) were significantly (p < 0.05, each) worse in mice fed either TMAO or choline supplemented diets compared to the control diet. In addition, myocardial fibrosis was also significantly greater (p < 0.01, each) in the TMAO and choline groups relative to controls.
Conclusions
Heart failure severity is significantly enhanced in mice fed diets supplemented in either choline or the gut microbe-dependent metabolite TMAO. The present results suggest that further studies are warranted examining whether gut microbiota and the dietary choline -> TMAO pathway contribute to increased heart failure susceptibility.
doi:10.1161/CIRCHEARTFAILURE.115.002314
PMCID: PMC4943035  PMID: 26699388
metabolomics; left ventricular dysfunction; fibrosis; pulmonary edema; transverse aortic constriction; choline
18.  One-Year Outcomes After Transcatheter Insertion of an Interatrial Shunt Device for the Management of Heart Failure With Preserved Ejection Fraction 
Circulation. Heart Failure  2016;9(12):e003662.
Supplemental Digital Content is available in the text.
Background—
Heart failure with preserved ejection fraction has a complex pathophysiology and remains a therapeutic challenge. Elevated left atrial pressure, particularly during exercise, is a key contributor to morbidity and mortality. Preliminary analyses have demonstrated that a novel interatrial septal shunt device that allows shunting to reduce the left atrial pressure provides clinical and hemodynamic benefit at 6 months. Given the chronicity of heart failure with preserved ejection fraction, evidence of longer-term benefit is required.
Methods and Results—
Patients (n=64) with left ventricular ejection fraction ≥40%, New York Heart Association class II–IV, elevated pulmonary capillary wedge pressure (≥15 mm Hg at rest or ≥25 mm Hg during supine bicycle exercise) participated in the open-label study of the interatrial septal shunt device. One year after interatrial septal shunt device implantation, there were sustained improvements in New York Heart Association class (P<0.001), quality of life (Minnesota Living with Heart Failure score, P<0.001), and 6-minute walk distance (P<0.01). Echocardiography showed a small, stable reduction in left ventricular end-diastolic volume index (P<0.001), with a concomitant small stable increase in the right ventricular end-diastolic volume index (P<0.001). Invasive hemodynamic studies performed in a subset of patients demonstrated a sustained reduction in the workload corrected exercise pulmonary capillary wedge pressure (P<0.01). Survival at 1 year was 95%, and there was no evidence of device-related complications.
Conclusions—
These results provide evidence of safety and sustained clinical benefit in heart failure with preserved ejection fraction patients 1 year after interatrial septal shunt device implantation. Randomized, blinded studies are underway to confirm these observations.
Clinical Trial Registration—
URL: https://www.clinicaltrials.gov. Unique identifier: NCT01913613.
doi:10.1161/CIRCHEARTFAILURE.116.003662
PMCID: PMC5175994  PMID: 27852653
heart failure; hemodynamics; physiology; therapeutics
19.  Physical Fitness and Risk for Heart Failure and Coronary Artery Disease 
Circulation. Heart failure  2013;6(4):627-634.
Background
Multiple studies have demonstrated strong associations between cardiorespiratory fitness and lower cardiovascular disease mortality. In contrast, little is known about associations of fitness with non-fatal cardiovascular events.
Methods and Results
Linking individual participant data from the Cooper Center Longitudinal Study with Medicare claims files, we studied 20,642 participants (21% women) with fitness measured at mean age 49 years and who survived to receive Medicare coverage from 1999 to 2009. Fitness was categorized into age- and sex-specific quintiles (Q) according to Balke protocol treadmill time with Q1 as low fitness. Fitness was also estimated in metabolic equivalents according to treadmill time. Associations between midlife fitness and hospitalizations for heart failure and acute myocardial infarction after age 65 were assessed by applying a proportional hazards model to the multivariate failure time data. After 133,514 person-years of Medicare follow-up, we observed 1,051 hospitalizations for heart failure and 832 hospitalizations for acute myocardial infarction. Compared to high fitness (Q4-5), low fitness (Q1) was associated with a higher rate of heart failure hospitalization (14.3% vs. 4.2%) and hospitalization for myocardial infarction (9.7% vs. 4.5%). After multivariable adjustment for baseline age, blood pressure, diabetes, body mass index, smoking status and total cholesterol, a 1 unit greater fitness level in metabolic equivalents (METs) achieved in midlife was associated with approximately a 20% lower risk for heart failure hospitalization after age 65 [Men, hazard ratio (95% confidence intervals): 0.79 (0.75-0.83), p<0.001; Women: 0.81 (0.68-0.96), P=0.01] but just a 10% lower risk for acute myocardial infarction in men [0.91 (0.87-0.95), p< 0.001] and no association in women [0.97 (0.83-1.13), p=0.68].
Conclusions
Fitness in healthy, middle-aged adults is more strongly associated with heart failure hospitalization than acute myocardial infarction outcomes decades later in older age.
doi:10.1161/CIRCHEARTFAILURE.112.000054
PMCID: PMC5152944  PMID: 23677924
cardiorespiratory fitness; heart failure; acute myocardial infarction
20.  HDACs Regulate miR-133a Expression in Pressure Overload Induced Cardiac Fibrosis 
Circulation. Heart failure  2015;8(6):1094-1104.
Background
MicroRNAs (miRNAs) and histone deacetylases (HDACs) serve a significant role in the pathogenesis of a variety of cardiovascular diseases. The transcriptional regulation of miRNAs is poorly understood in cardiac hypertrophy. We investigated whether the expression of miR-133a is epigenetically regulated by Class I and IIb HDACs during hypertrophic remodeling.
Methods and Results
Transverse aortic constriction (TAC) was performed in CD1 mice to induce pressure overload (PO) hypertrophy. Mice were treated with Class I and IIb HDAC inhibitor via drinking water for 2 and 4 weeks post-TAC. miRNA expression was determined by real time PCR. Echocardiography was performed at baseline and post-TAC endpoints for structural and functional assessment. Chromatin immunoprecipitation (ChIP) was used to identify HDACs and transcription factors associated with miR-133a promoter. miR-133a expression was downregulated by 0.7 and 0.5 fold at 2 weeks and 4 weeks post-TAC respectively as compared to vehicle-control (P < 0.05). HDAC inhibition prevented this significant decrease 2 weeks post-TAC and maintained miR-133a expression near vehicle-control levels, which coincided with 1) a decrease in connective tissue growth factor (CTGF) expression, 2) a reduction in cardiac fibrosis and left atrium diameter (marker of end-diastolic pressure) suggesting an improvement in diastolic function. ChIP analysis revealed that HDAC1 and HDAC2 are present on the miR-133a enhancer regions.
Conclusions
The results reveal that HDACs play a role in the regulation of PO-induced miR-133a downregulation. This work is the first to provide insight into an epigenetic-miRNA regulatory pathway in PO-induced cardiac fibrosis.
doi:10.1161/CIRCHEARTFAILURE.114.001781
PMCID: PMC4651803  PMID: 26371176
microRNA; epigenetics; hypertrophy/remodeling; transcription regulation; HDAC; miR-133a
21.  Cardiac Resynchronization Therapy Reduces Subcellular Heterogeneity of Ryanodine Receptors, T-Tubules and Ca2+ Sparks Produced by Dyssynchronous Heart Failure 
Circulation. Heart failure  2015;8(6):1105-1114.
Background
Cardiac resynchronization therapy (CRT) is a major advance for treatment of patients with dyssynchronous heart failure (DHF). However, our understanding of DHF-associated remodeling of subcellular structure and function and their restoration after CRT remains incomplete.
Methods and Results
We investigated subcellular heterogeneity of remodeling of structures and proteins associated with excitation-contraction coupling in cardiomyocytes in DHF and after CRT. Three-dimensional confocal microscopy revealed subcellular heterogeneity of ryanodine receptor (RyR) density and the transverse tubular system (t-system) in a canine model of DHF. RyR density at the ends of lateral left ventricular cardiomyocytes was higher than in cell centers, while the t-system was depleted at cell ends. In anterior left ventricular cardiomyocytes, however, we found a similar degree of heterogeneous RyR remodeling despite preserved t-system. Synchronous heart failure (SHF) was associated with marginal heterogeneity of RyR density. We used rapid scanning confocal microscopy to investigate effects of heterogeneous structural remodeling on calcium signaling. In DHF, diastolic Ca2+ spark density was smaller at cell ends versus centers. After CRT, subcellular heterogeneity of structures and function was reduced.
Conclusions
RyR density exhibits remarkable subcellular heterogeneity in DHF. RyR remodeling occurred in lateral and anterior cardiomyocytes, but remodeling of t-system was confined to lateral myocytes. These findings indicate that different mechanisms underlie remodeling of RyRs and t-system. Furthermore, we suggest that ventricular dyssynchrony exacerbates subcellular remodeling in heart failure. CRT efficiently reduced subcellular heterogeneity. These results will help to explain remodeling of EC coupling in disease and restoration after CRT.
doi:10.1161/CIRCHEARTFAILURE.115.002352
PMCID: PMC4651794  PMID: 26294422
remodeling heart failure; cardiac resynchronization therapy; myocyte; ryanodine receptors; excitation-contraction coupling; transverse tubular system
22.  PPARα Association With Sirt1 Suppresses Cardiac Fatty Acid Metabolism in the Failing Heart 
Circulation. Heart failure  2015;8(6):1123-1132.
Background
Heart failure (HF) is accompanied by changes in cardiac metabolism characterized by reduced fatty acid (FA) utilization. However, the underlying mechanism and its causative involvement in the progression of HF are poorly understood. The peroxisome proliferator activated receptor-α (PPARα)/retinoid X receptor (RXR) heterodimer promotes transcription of genes involved in FA metabolism through binding to the PPAR response element, called direct repeat 1 (DR1). Silent information regulator 1 (Sirt1) is a histone deacetylase which interacts with PPARα.
Methods and Results
To investigate the role of PPARα in the impaired FA utilization observed during HF, genetically altered mice were subjected to pressure overload (PO). The DNA binding of PPARα, RXRα and Sirt1 to DR1 was evaluated with oligonucleotide pull-down and chromatin immunoprecipitation assays. Although the binding of PPARα to DR1 was enhanced in response to PO, that of RXRα was attenuated. Sirt1 competes with RXRα to dimerize with PPARα, thereby suppressing FA utilization in the failing heart. DR1 sequence analysis indicated that the typical DR1 sequence favors PPARα/RXRα heterodimerization, whereas the switch from RXRα to Sirt1 takes place on degenerate DR1s. Sirt1 bound to PPARα through a region homologous to the PPARα binding domain in RXRα. A short peptide corresponding to the RXRα domain not only inhibited the interaction between PPARα and Sirt1 but also improved FA metabolism and ameliorated cardiac dysfunction.
Conclusions
A change in the heterodimeric partner of PPARα from RXRα to Sirt1 is responsible for the impaired FA metabolism and cardiac dysfunction in the failing heart.
doi:10.1161/CIRCHEARTFAILURE.115.002216
PMCID: PMC4651813  PMID: 26443578
heart failure; metabolism; transcription
23.  A Molecular Screen Identifies Cardiac Myosin Binding Protein-C as a Protein Kinase G I Alpha Substrate 
Circulation. Heart failure  2015;8(6):1115-1122.
Background
Pharmacologic activation of cGMP-dependent protein kinase I (PKGI) has emerged as a therapeutic strategy for humans with heart failure. However, PKG activating drugs have been limited by hypotension arising from PKG-induced vasodilation. PKGIα anti-remodeling substrates specific to the myocardium might provide targets to circumvent this limitation, but currently remain poorly understood.
Methods and Results
We performed a screen for myocardial proteins interacting with the PKGIα leucine zipper (LZ) binding domain to identify myocardial-specific PKGI anti-remodeling substrates. Our screen identified cardiac myosin binding protein C (cMyBP-C), a cardiac myocyte-specific protein, which has been demonstrated to inhibit cardiac remodeling in the phosphorylated state, and when mutated leads to hypertrophic cardiomyopathy in humans. GST-pulldowns and precipitations with cGMP-conjugated beads confirmed the PKGIα-cMyBP-C interaction in myocardial lysates. In vitro studies demonstrated that purified PKGIα phosphorylates the cMyBP-C M-domain at Ser-273, Ser-282, and Ser-302. cGMP induced cMyBP-C phosphorylation at these residues in COS cells transfected with PKGIα, but not in cells transfected with LZ mutant PKGIα containing mutations to disrupt LZ substrate binding. In mice subjected to LV pressure overload, PKGI activation with sildenafil increased cMyBP-C phosphorylation at Ser-273 compared with untreated mice. cGMP also induced cMyBP-C phosphorylation in isolated cardiac myocytes.
Conclusions
Taken together these data support that PKGIα and cMyBP-C interact in the heart, and that cMyBP-C is an anti-remodeling PKGIα kinase substrate. This study provides the first identification of a myocardial specific PKGIα LZ-dependent anti-remodeling substrate and supports further exploration of PKGIα myocardial LZ substrates as potential therapeutic targets for heart failure.
doi:10.1161/CIRCHEARTFAILURE.115.002308
PMCID: PMC4651836  PMID: 26477830
cGMP; cardiac remodeling; heart failure; myosin binding protein
24.  Elevated Plasma Marinobufagenin, An Endogenous Cardiotonic Steroid, Is Associated with Right Ventricular Dysfunction and Nitrative Stress in Heart Failure 
Circulation. Heart failure  2015;8(6):1068-1076.
Background
Plasma levels of cardiotonic steroids (CTS) are elevated in volume-expanded states such as chronic kidney disease, but the role of these natriuretic hormones in subjects with heart failure (HF) is unclear. We sought to determine the prognostic role of the CTS marinobufagenin (MBG) in HF, particularly in relation to long-term outcomes.
Methods and Results
We first measured plasma MBG levels and performed comprehensive clinical, laboratory, and echocardiographic assessment in 245 HF patients. All-cause mortality, cardiac transplantation, and HF hospitalization were tracked for 5 years. In our study cohort, median [interquartile range] MBG was 583 [383-812] pM. Higher MBG was associated with higher myeloperoxidase (MPO, r=0.42, p<0.0001), BNP (r=0.25, p=0.001), and asymmetric dimethylarginine (ADMA, r=0.32, p<0.001). Elevated levels of MBG were associated with measures of worse right ventricular function (RV s’: r= −0.39, p<0.0001) and predicted increased risk of adverse clinical outcomes (MBG ≥574 pM: HR 1.58 [1.10-2.31], p=0.014) even after adjustment for age, gender, diabetes mellitus, and ischemic etiology. In mice, a left anterior descending coronary artery ligation model of heart failure lead to increases in MBG, while infusion of MBG into mice for 4 weeks lead to significant increases in MPO, ADMA, and cardiac fibrosis.
Conclusions
In the setting of heart failure, elevated plasma levels of MBG are associated with right ventricular dysfunction and predict worse long-term clinical outcomes in multivariable models adjusting for established clinical and biochemical risk factors. Infusion of MBG appears to directly contribute to increased nitrative stress and cardiac fibrosis.
doi:10.1161/CIRCHEARTFAILURE.114.001976
PMCID: PMC4651837  PMID: 26276886
heart failure; cardiotonic steroids; outcome; nitrative stress; cardiac fibrosis

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