Journal: Circ Heart Fail

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Abstract

Postnatal Loss of Kindlin-2 Leads to Progressive Heart Failure.

Zhang Z, Mu Y, Veevers J, Peter AK, ... Zhou X, Chen J
The striated muscle costamere, a multiprotein complex at the boundary between the sarcomere and the sarcolemma, plays an integral role in maintaining striated muscle structure and function. Multiple costamere-associated proteins, such as integrins and integrin-interacting proteins, have been identified and shown to play an increasingly important role in the pathogenesis of human cardiomyopathy. Kindlin-2 is an adaptor protein that binds to the integrin β cytoplasmic tail to promote integrin activation. Genetic deficiency of Kindlin-2 results in embryonic lethality, and knockdown of the Kindlin-2 homolog in Caenorhabditis elegans and Danio rerio suggests that it has an essential role in integrin function and normal muscle structure and function. The precise role of Kindlin-2 in the mammalian cardiac myocyte remains to be determined.

Circ Heart Fail: 08 Aug 2016; 9
Zhang Z, Mu Y, Veevers J, Peter AK, ... Zhou X, Chen J
Circ Heart Fail: 08 Aug 2016; 9 | PMID: 27502369
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Abstract

Novel Approach Targeting the Complex Pathophysiology of Hypertrophic Cardiomyopathy: The Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) Trial.

Olivotto I, Hellawell JL, Farzaneh-Far R, Blair C, ... Belardinelli L, Maron MS
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder, with an overall prevalence of at least 1:500 in the adult population although only a fraction of affected patients come to clinical recognition. It is also the most common cause of sudden cardiac death in young adults and a major cause of morbidity caused by chronic heart failure symptoms. However, more than half a century since the original description of the disease, there is no currently approved therapy for the treatment of patients with HCM, and to date there have been only 5 randomized studies of medical therapies in HCM. As such, unmet medical need in HCM has been highlighted by the National Heart, Lung, and Blood Institute (NHLBI) as a research priority. Encouragingly, the infrastructure needed to conduct rigorous clinical trials in HCM has recently emerged because of the heightened awareness and understanding of the disease, development of clinical centers of excellence, and advances in diagnostic imaging. In this article, we will discuss the complex pathophysiology of HCM, review the current therapeutic landscape, describe new mechanistic insights into the central role of the late sodium current in HCM, and introduce the scientific rationale and execution of the Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) trial, the largest randomized, double-blind, placebo controlled clinical trial, now underway, designed to evaluate the effect of a novel pharmacological approach in patients with symptomatic HCM.

Circ Heart Fail: 25 Feb 2016; 9:e002764
Olivotto I, Hellawell JL, Farzaneh-Far R, Blair C, ... Belardinelli L, Maron MS
Circ Heart Fail: 25 Feb 2016; 9:e002764 | PMID: 26915375
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Abstract

Matching the Market for Heart Transplantation.

Hsich EM
Heart transplantation is the most effective therapy for patients with Stage D heart failure with a median life expectancy of ≈10 to 15 years. Unfortunately, many patients die on the waiting list hoping for a chance of survival. The life boat cannot rescue everyone. Over a decade, the donor pool has remained relatively stable, whereas the number of heart transplant candidates has risen. Potential recipients often have many comorbidities and are older because the criteria for heart transplantation has few absolute contraindications. Women, Hispanics, and patients with restrictive heart disease and congenital heart disease are more likely to die while awaiting heart transplantation than men, white patients, and those with either ischemic or dilated cardiomyopathy. To better match the market, we need to (1) increase the donor pool, (2) reduce the waitlist, and (3) improve the allocation system. This review article addresses all 3 options and compares strategies in the United States to those in other countries.

Circ Heart Fail: 12 Apr 2016; 9
Hsich EM
Circ Heart Fail: 12 Apr 2016; 9 | PMID: 27072859
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Abstract

Developing New Treatments for Heart Failure: Focus on the Heart.

Gheorghiade M, Larson CJ, Shah SJ, Greene SJ, ... Sabbah HN, Butler J
Compared with heart failure (HF) care 20 to 30 years ago, there has been tremendous advancement in therapy for ambulatory HF with reduced ejection fraction with the use of agents that block maladaptive neurohormonal pathways. However, during the past decade, with few notable exceptions, the frequency of successful drug development programs has fallen as most novel therapies have failed to offer incremental benefit or raised safety concerns (ie, hypotension). Moreover, no therapy has been approved specifically for HF with preserved ejection fraction or for worsening chronic HF (including acutely decompensated HF). Across the spectrum of HF, preliminary results from many phase II trials have been promising but are frequently followed by unsuccessful phase III studies, highlighting a disconnect in the translational process between basic science discovery, early drug development, and definitive clinical testing in pivotal trials. A major unmet need in HF drug development is the ability to identify homogeneous subsets of patients whose underlying disease is driven by a specific mechanism that can be targeted using a new therapeutic agent. Drug development strategies should increasingly consider therapies that facilitate reverse remodeling by directly targeting the heart itself rather than strictly focusing on agents that unload the heart or target systemic neurohormones. Advancements in cardiac imaging may allow for more focused and direct assessment of drug effects on the heart early in the drug development process. To better understand and address the array of challenges facing current HF drug development, so that future efforts may have a better chance for success, the Food and Drug Administration facilitated a meeting on February 17, 2015, which was attended by clinicians, researchers, regulators, and industry representatives. The following discussion summarizes the key takeaway dialogue from this meeting.

Circ Heart Fail: 10 May 2016; 9
Gheorghiade M, Larson CJ, Shah SJ, Greene SJ, ... Sabbah HN, Butler J
Circ Heart Fail: 10 May 2016; 9 | PMID: 27166246
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Abstract

Impaired Mitochondrial Biogenesis Precedes Heart Failure in Right Ventricular Hypertrophy in Congenital Heart Disease.

Karamanlidis G, Bautista-Hernandez V, Fynn-Thompson F, Del Nido P, Tian R
Background: -The outcome of the surgical repair in congenital heart disease (CHD) correlates with the degree of myocardial damage. In this study we determined whether mitochondrial DNA depletion is a sensitive marker of right ventricular (RV) damage and whether impaired mitochondrial DNA (mtDNA) replication contributes to the transition from compensated hypertrophy to failure. Methods and results: -RV samples obtained from 31 patients undergoing cardiac surgery were compared to 5 RV samples from non-failing hearts (control). Patients were divided into compensated hypertrophy and failure groups based on preoperative echocardiography, catheterization and/or MRI data. Mitochondrial enzyme activities (citrate synthase and succinate dehydrogenase) were maintained during hypertrophy and decreased by ~40% (p<0.05 vs. control) at the stage of failure. In contrast, mtDNA content was progressively decreased in the hypertrophied RV through failure (by 28±8% and 67±11% respectively, p<0.05 for both), whereas mtDNA encoded gene expression was sustained by increased transcriptional activity during compensated hypertrophy but not in failure. MtDNA depletion was attributed to reduced mtDNA replication in both hypertrophied and failing RV and it was independent of PGC-1 down-regulation but was accompanied by reduced expression of proteins constituting the mtDNA replication fork. Decreased mtDNA content in compensated hypertrophy was also associated with pathological changes of mitochondria ultrastructure. Conclusions: -Impaired mtDNA replication causes early and progressive depletion of mtDNA in the RV of the CHD patients during the transition from hypertrophy to failure. Decreased mtDNA content is likely a sensitive marker of mitochondrial injury in this patient population.

Circ Heart Fail: 15 Aug 2011; epub ahead of print
Karamanlidis G, Bautista-Hernandez V, Fynn-Thompson F, Del Nido P, Tian R
Circ Heart Fail: 15 Aug 2011; epub ahead of print | PMID: 21840936
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Abstract

Usefulness of Carvedilol in the Treatment of Chronic Aortic Valve Regurgitation.

Zendaoui A, Lachance D, Roussel E, Couet J, Arsenault M
Background: -Aortic regurgitation (AR) is a chronic disease for which there is currently no approved medical treatment. We previously reported in an animal model that beta blockade with metoprolol exerted beneficial effects on LV remodeling and survival. Despite the recent publication of promising human data beta blockade in chronic AR still remains controversial. More data is needed to support this potentially new treatment strategy. We hypothesized that carvedilol (CAR) might be another safe treatment option in chronic AR considering its combined beta and alpha blocking effects and proven efficacy in patients with established heart failure. Methods and results: -The effects of a 6-month treatment with carvedilol 30 mg/kg/day orally were evaluated in adult Wistar rats with severe AR. Sham-operated and untreated AR animals were used as controls. Carvedilol treatment resulted in less left ventricular hypertrophy and dilatation. Ejection fraction was improved and filling pressures were reduced by carvedilol. β1 receptor expression was also improved as well as myocardial capillary density. Those beneficial effects were noted despite the presence of drug-induced bradycardia. Conclusions: -Carvedilol exerted protective effects against volume-overload cardiomyopathy in this model of aortic valve regurgitation with preserved ejection fraction. These results suggest a protective class-effect of beta-blockers. Combined with the recent publication of promising human data, our findings support the need to carefully design a prospective study in humans to evaluate the effects of beta blockers in chronic aortic valve regurgitation.

Circ Heart Fail: 10 Jan 2011; epub ahead of print
Zendaoui A, Lachance D, Roussel E, Couet J, Arsenault M
Circ Heart Fail: 10 Jan 2011; epub ahead of print | PMID: 21216836
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Abstract

Fluid Volume Overload and Congestion in Heart Failure: Time to Reconsider Pathophysiology and How Volume Is Assessed.

Miller WL
Volume regulation, assessment, and management remain basic issues in patients with heart failure. The discussion presented here is directed at opening a reassessment of the pathophysiology of congestion in congestive heart failure and the methods by which we determine volume overload status. Peer-reviewed historical and contemporary literatures are reviewed. Volume overload and fluid congestion remain primary issues for patients with chronic heart failure. The pathophysiology is complex, and the simple concept of intravascular fluid accumulation is not adequate. The dynamics of interstitial and intravascular fluid compartment interactions and fluid redistribution from venous splanchnic beds to central pulmonary circulation need to be taken into account in strategies of volume management. Clinical bedside evaluations and right heart hemodynamic assessments can alert clinicians of changes in volume status, but only the quantitative measurement of total blood volume can help identify the heterogeneity in plasma volume and red blood cell mass that are features of volume overload in patients with chronic heart failure and help guide individualized, appropriate therapy-not all volume overload is the same.

Circ Heart Fail: 19 Jul 2016; 9:e002922
Miller WL
Circ Heart Fail: 19 Jul 2016; 9:e002922 | PMID: 27436837
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Abstract

Changes in Ion Channel Gene Expression Underlying Heart Failure-induced Sinoatrial Node Dysfunction.

Yanni J, Tellez JO, Maczewski M, Mackiewicz U, ... Dobrzynski H, Boyett MR
Background: -Heart failure (HF) causes a decline in the function of the pacemaker of the heart, the sinoatrial node (SAN). The aim of the study was to investigate HF-induced changes in the expression of the ion channels and related proteins underlying the pacemaker activity of the SAN. Methods and results: -HF was induced in rats by the ligation of the proximal left coronary artery. HF animals showed an increase in the left ventricular diastolic pressure (317%) and a decrease in the left ventricular systolic pressure (19%) in comparison to sham-operated animals. They also showed SAN dysfunction: the intrinsic heart rate was reduced (16%) and the corrected SAN recovery time was increased (56%). qPCR was used to measure gene expression. During HF, of the 91 genes studied, 58% changed in the SAN, although only 1% changed in the atrial muscle. For example, there was an increase in the expression of ERG, K(v)LQT1, K(ir)2.4, TASK1, TWIK1/2, calsequestrin 2 and the A1 adenosine receptor in the SAN and this could explain the slowing of the intrinsic heart rate. In addition, there was an increase in NHE1 and this could be the stimulus for the remodelling of the SAN. Conclusions: -SAN dysfunction is associated with HF and is the result of an extensive remodelling of ion channels, gap junction channels, Ca(2+)-, Na(+)- and H(+)-handling proteins, and receptors in the SAN.

Circ Heart Fail: 13 May 2011; epub ahead of print
Yanni J, Tellez JO, Maczewski M, Mackiewicz U, ... Dobrzynski H, Boyett MR
Circ Heart Fail: 13 May 2011; epub ahead of print | PMID: 21565973
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Abstract

The Relationship Between Reactive Pulmonary Hypertension and Mortality In Patients With Acute Decompensated Heart Failure.

Aronson D, Eitan A, Dragu R, Burger AJ
Background: -In patients with heart failure, pulmonary hypertension (PH) predicts higher risk for morbidity and mortality. However, few data are available on the prognostic implications of reactive (pre-capillary) PH superimposed on passive (post-capillary) PH. Methods and results: -We performed a subgroup analysis of 242 patients with acute decompensated heart failure (ADHF) assigned to pulmonary artery catheter placement in the Vasodilation in the Management of Acute Congestive Heart Failure trial. Patients were classified into 3 groups using the final (post-treatment) hemodynamic measurements: (1) no PH (mean PA pressure [mPAP]≤25 mm Hg, (2) passive PH (mPAP>25, pulmonary capillary wedge pressure [PCWP]>15 mm Hg and pulmonary vascular resistance [PVR]≤3 Wood units), and (3) reactive PH (mPAP≥25, PCWP>15 mm Hg and PVR>3 Wood Units). Fifty eight patients were classified as normal mPAP, 124 with passive PH and 60 with reactive PH. During follow-up of 6-months, 5 (8.6%), 27 (21.8%), and 29 (48.3%) deaths occurred in patients without PH, patients with passive PH, and with reactive PH, respectively (P<0.0001). After multivariable adjustments, reactive PH remained an independent predictor of mortality with an adjusted hazard ratio of 4.8 as compared to patients without PH, and 2.8 compared with patients with passive PH (95% CI 1.7-4.7, P=0.0001). Similar results were obtained when reactive PH was defined based on the transpulmonary gradient. Conclusions: -Reactive PH is common among patients with ADHF after initial diuretic and vasodilator therapy. The adverse outcome associated with PH is predominantly due to increased mortality in the subgroup of patients with reactive PH.

Circ Heart Fail: 24 May 2011; epub ahead of print
Aronson D, Eitan A, Dragu R, Burger AJ
Circ Heart Fail: 24 May 2011; epub ahead of print | PMID: 21606213
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Abstract

Nuclear Effects of GRK5 on HDAC5-regulated Gene Transcription in Heart Failure.

Zhang Y, Matkovich SJ, Duan X, Gold JI, Koch WJ, Dorn GW
Background: -G-protein receptor kinases (GRKs) modulate cardiac β-adrenergic signaling. GRK5 is upregulated in heart failure, and a gain-of-function polymorphism substituting leucine for wild-type glutamine at amino acid 41 (GRK5-Leu41) is associated with improved outcomes in heart failure and hypertension. GRK5 is distinguished by partial nuclear localization and HDAC kinase activity that is postulated to regulate Gαq-stimulated cardiac gene expression. Methods and results: -We used in vitro tissue culture and in vivo mouse compound genetic models to examine the effects of GRK5 on HDAC phosphorylation, nucleo-cytoplasmic HDAC transport, and Gαq-dependent transcriptional regulation. In vitro, GRK5 stimulated HDAC5 nuclear export only in the context of Gαq signaling stimulated by angiotensin II. GRK5-Gln41 and Leu41 were similar inducers of HDAC5 nucleo-cytoplasmic shuttling. In vivo, GRK5-Gln41 and-Leu41 partitioned equally to nuclear and non-nuclear myocardial fractions. GRK5 increased cardiac HDAC5 phosphorylation and reversed the increase in nuclear HDAC5 content seen with cardiomyocyte-autonomous Gαq overexpression. Deep RNA sequencing showed few changes in gene expression induced by GRK5 overexpression or ablation alone, but GRK5 overexpression normalized steady-state expression levels of 48% (96 of 200) of all Gαq down-regulated mRNAs. Conclusions: -GRK5 is a transcriptional modifier of a sub-set of Gαq-downregulated genes, acting in opposition to the pathological effects of Gαq and normalizing levels of these transcripts. This transcriptional co-regulator effect may act in concert with β-adrenergic receptor desensitization to protect against heart failure decompensation.

Circ Heart Fail: 19 Jul 2011; epub ahead of print
Zhang Y, Matkovich SJ, Duan X, Gold JI, Koch WJ, Dorn GW
Circ Heart Fail: 19 Jul 2011; epub ahead of print | PMID: 21768220
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Abstract

Transthyretin Cardiac Amyloidosis in Black Americans.

Shah KB, Mankad AK, Castano A, Akinboboye OO, ... Fergus IV, Maurer MS
Transthyretin-related cardiac amyloidosis is a progressive infiltrative cardiomyopathy that mimics hypertensive and hypertrophic heart disease and often goes undiagnosed. In the United States, the hereditary form disproportionately afflicts black Americans, who when compared with whites with wild-type transthyretin amyloidosis, a phenotypically similar condition, present with more advanced disease despite having a noninvasive method for early identification (genetic testing). Although reasons for this are unclear, this begs to consider the inadequate access to care, societal factors, or a biological basis. In an effort to improve awareness and explore unique characteristics, we review the pathophysiology, epidemiology, and therapeutic strategies for transthyretin amyloidosis and highlight diagnostic pitfalls and clinical pearls for identifying patients with amyloid heart disease.

Circ Heart Fail: 17 May 2016; 9:e002558
Shah KB, Mankad AK, Castano A, Akinboboye OO, ... Fergus IV, Maurer MS
Circ Heart Fail: 17 May 2016; 9:e002558 | PMID: 27188913
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Abstract

Oral Iron Therapy for Heart Failure With Reduced Ejection Fraction: Design and Rationale for Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure.

Lewis GD, Semigran MJ, Givertz MM, Malhotra R, ... Shah MR, Braunwald E
: Iron deficiency is present in ≈50% of patients with heart failure and is an independent predictor of mortality. Despite growing recognition of the functional and prognostic significance of iron deficiency, randomized multicenter trials exploring the use of oral iron supplementation in heart failure, a therapy that is inexpensive, readily available, and safe, have not been performed. Moreover, patient characteristics that influence responsiveness to oral iron in patients with heart failure have not been defined. Although results of intravenous iron repletion trials have been promising, regularly treating patients with intravenous iron products is both expensive and poses logistical challenges for outpatients. Herein, we describe the rationale for the Oral Iron Repletion effects on Oxygen Uptake in Heart Failure (IRONOUT HF) trial. This National Institute of Health-sponsored trial will investigate oral iron polysaccharide compared with matching placebo with the primary end point of change in exercise capacity as measured by peak oxygen consumption at baseline and at 16 weeks.

Circ Heart Fail: 02 May 2016; 9
Lewis GD, Semigran MJ, Givertz MM, Malhotra R, ... Shah MR, Braunwald E
Circ Heart Fail: 02 May 2016; 9 | PMID: 27140203
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Abstract

Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure: Rationale and Design of the Randomized Trial to REDUCE Elevated Left Atrial Pressure in Heart Failure (REDUCE LAP-HF I).

Feldman T, Komtebedde J, Burkhoff D, Massaro J, ... Mauri L, Shah SJ
Heart failure with preserved ejection fraction (HFpEF), a major public health problem with high morbidity and mortality rates, remains difficult to manage because of a lack of effective treatment options. Although HFpEF is a heterogeneous clinical syndrome, elevated left atrial pressure-either at rest or with exertion-is a common factor among all forms of HFpEF and one of the primary reasons for dyspnea and exercise intolerance in these patients. On the basis of clinical experience with congenital interatrial shunts in mitral stenosis, it has been hypothesized that the creation of a left-to-right interatrial shunt to decompress the left atrium (without compromising left ventricular filling or forward cardiac output) is a rational, nonpharmacological strategy for alleviating symptoms in patients with HFpEF. A novel transcatheter interatrial shunt device has been developed and evaluated in patients with HFpEF in single-arm, nonblinded clinical trials. These studies have demonstrated the safety and potential efficacy of the device. However, a randomized, placebo-controlled evaluation of the device is required to further evaluate its safety and efficacy in patients with HFpEF. In this article, we give the rationale for a therapeutic transcatheter interatrial shunt device in HFpEF, and we describe the design of REDUCE Elevated Left Atrial Pressure in Heart Failure (REDUCE LAP-HF I), the first randomized controlled trial of a device-based therapy to reduce left atrial pressure in HFpEF.

Circ Heart Fail: 21 Jun 2016; 9
Feldman T, Komtebedde J, Burkhoff D, Massaro J, ... Mauri L, Shah SJ
Circ Heart Fail: 21 Jun 2016; 9 | PMID: 27330010
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Abstract

Atrial Fibrillation and Mortality in Heart Failure: A Community Study.

Chamberlain AM, Redfield MM, Alonso A, Weston SA, Roger VL
Background: -Heart failure (HF) and atrial fibrillation (AF) share common risk factors and often coexist. The combination of HF and AF may carry a worse prognosis than either condition alone; however, the magnitude of this risk remains controversial and it is not known whether the timing of AF influences the risk of death. Methods and results: -We determined the risk of all-cause mortality in relation to the presence of AF prior to or after HF diagnosis in a community-based cohort of persons diagnosed with HF between 1983 and 2006. Of 1664 individuals with HF, 553 had a prior history of AF and 384 developed AF after HF. Over a median follow-up of 4.0 years, 450 deaths occurred among persons with prior AF, 314 among those with AF after HF, and 572 among patients without AF. In fully-adjusted models, compared to patients without AF, those with AF prior to HF had a 29% increased risk of death, while those who developed AF after HF exhibited more than a 2-fold increased risk of death. Conclusions: -In the community, AF is frequent in the setting of HF and is associated with a large excess risk of death. The magnitude of this excess risk differs markedly according to the timing of AF, with AF developing after HF conferring the largest increased risk of death compared to HF patients without AF.

Circ Heart Fail: 16 Sep 2011; epub ahead of print
Chamberlain AM, Redfield MM, Alonso A, Weston SA, Roger VL
Circ Heart Fail: 16 Sep 2011; epub ahead of print | PMID: 21920917
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Abstract

CXCR4 Antagonism Attenuates the Cardiorenal Consequences of Mineralocorticoid Excess.

Chu PY, Zatta A, Kiriazis H, Chin-Dusting J, ... Marshall T, Kaye DM
Background: -Extensive evidence implicates aldosterone excess in the development and progression of cardiovascular disease states including hypertension, metabolic syndrome, cardiac hypertrophy, heart failure and cardiorenal fibrosis. Recent studies show that activation of inflammatory cascade may play a specific role in the sequelae of mineralocorticoid activation, although the linking mechanism remains unclear. Here we tested the possibility that secondary stimulation of the SDF-1 (stromal derived factor 1)/CXCR4 (CXC chemokine receptor 4) pathway plays a contributory role. Methods and results: -We investigated the effect of the highly selective CXCR4 antagonist AMD3465 (6 mg/kg/day for 6 weeks via minipump) in DOCA treated, uninephrectomized mice. CXCR4 antagonism significantly attenuated the induction of cardiac fibrosis, renal fibrosis, hypertension and left ventricular hypertrophy by DOCA. Mineralocorticoid excess also stimulated the accumulation of T-lymphocytes in the heart and kidney and this was significantly blunted by CXCR4 inhibition. Conclusions: -Taken together these data strongly implicate the SDF-1/CXCR4 axis in the pathogenesis of mineralocorticoid excess induced hypertension, inflammation and cardio-renal fibrosis. This insight provides a new potential therapeutic approach for the treatment of specific aspects of mineralocorticoid mediated cardiovascular disease.

Circ Heart Fail: 20 Jun 2011; epub ahead of print
Chu PY, Zatta A, Kiriazis H, Chin-Dusting J, ... Marshall T, Kaye DM
Circ Heart Fail: 20 Jun 2011; epub ahead of print | PMID: 21685249
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Abstract

Effect of Peri-Infarct Pacing Early after Myocardial Infarction: Results of the Prevention of Myocardial Enlargement and Dilatation Post Myocardial Infarction (MENDMI) Study.

Chung ES, Dan D, Solomon SD, Bank AJ, ... Machado C, Stolen CM
Background: -Left ventricular (LV) remodeling has been attributed to the segmental loss of viable myocardium due to myocardial infarction (MI), which results in redistribution of cardiac workload, with increased regional wall stress in and around the infarct zone. Because ventricular pacing has been shown to reduce regional wall stress and workload in regions near the pacing site, this trial was designed to test if chronic pacing near the infarct attenuates LV remodeling. Methods and results: -Eighty patients with an anterior MI, peak Creatine Kinase >2000 mU/mL, ejection fraction ≤35%, wall motion abnormality (WMA) in >5/16 segments and QRS <120 ms, were randomized to either control (ICD) or bi-ventricular pacing with peri-infarct LV lead placement (CRT-D) arms between 2 and 14 days after the MI. The primary endpoint, change in LV end diastolic volume from baseline to 12 months, was not significantly different between the two groups (LVEDV: CRT, 10.6±27.7ml; ICD, 11.2±31.2ml; two-sample t-test p>0.05). In hypothesis-generating secondary analysis, there was a sustained reduction in the WMA score at 12 months in paced patients (CRT, -0.16±0.28 vs. ICD, -0.01±0.24, two-sample t-test p=0.03). No differences were found in the therapy related event rate, hospitalizations or mortality (all p>0.05). Conclusions: -Chronic pacing in the infarct region did not alter the primary endpoint of left ventricular remodeling over a year. Clinical trial registration-URL: http://clinicaltrials.gov. Unique Identifier: NCT00605631.

Circ Heart Fail: 20 Sep 2010; epub ahead of print
Chung ES, Dan D, Solomon SD, Bank AJ, ... Machado C, Stolen CM
Circ Heart Fail: 20 Sep 2010; epub ahead of print | PMID: 20852059
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Abstract

Junctophilin-2 Expression Silencing Causes Cardiocyte Hypertrophy and Abnormal Intracellular Calcium-Handling.

Landstrom AP, Kellen CA, Dixit SS, van Oort RJ, ... Wehrens XH, Ackerman MJ
Background: -Junctophilin-2 (JPH2), a protein expressed in the junctional membrane complex, is necessary for proper intracellular calcium (Ca(2+)) signaling in cardiac myocytes. Down-regulation of JPH2 expression in a model of cardiac hypertrophy was recently associated with defective coupling between plasmalemmal L-type Ca(2+) channels and sarcoplasmic reticular ryanodine receptors. However, it remains unclear whether JPH2 expression is altered in patients with hypertrophic cardiomyopathy (HCM). In addition, the effects of down-regulation of JPH2 expression on intracellular Ca(2+)-handling are presently poorly understood. We sought to determine whether loss of JPH2 expression is noted among patients with HCM and whether expression silencing might perturb Ca(2+)-handling in a pro-hypertrophic manner. Methods and results: -JPH2 expression was reduced in flash frozen human cardiac tissue procured from patients with HCM compared to ostensibly healthy traumatic death victims. Partial silencing of JPH2 expression in HL-1 cells by a small interfering RNA probe targeted to murine JPH2 mRNA (shJPH2) resulted in myocyte hypertrophy and increased expression of known markers of cardiac hypertrophy. While expression levels of major Ca(2+)-handling proteins were unchanged, shJPH2 cells demonstrated depressed maximal Ca(2+) transient amplitudes that were insensitive to LTCC activation with JPH2 knock-down. Further, reduced caffeine-triggered SR store Ca(2+) levels were observed with potentially increased total Ca(2+) stores. Spontaneous Ca(2+) oscillations were elicited at a higher extracellular [Ca(2+)] and with decreased frequency in JPH2 knock-down cells. Conclusions: -Our results show that JPH2 levels are reduced in patients with HCM. Reduced JPH2 expression results in reduced excitation-contraction coupling gain as well as altered Ca(2+) homeostasis which may be associated with pro-hypertrophic remodeling.

Circ Heart Fail: 10 Jan 2011; epub ahead of print
Landstrom AP, Kellen CA, Dixit SS, van Oort RJ, ... Wehrens XH, Ackerman MJ
Circ Heart Fail: 10 Jan 2011; epub ahead of print | PMID: 21216834
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Abstract

Decompensated Heart Failure is Associated with Reduced Corin Levels and Decreased Cleavage of Pro-Atrial Natriuretic Peptide.

Ibebuogu UN, Gladysheva IP, Houng AK, Reed GL
Background: -By promoting salt and water excretion, the corin and the atrial natriuretic peptide (ANP) system should help to maintain fluid balance in heart failure. Yet, the development of fluid retention despite high levels of ANP-related peptides, suggests that this compensatory system is limited. Methods and results: -Levels of circulating corin (the pro-ANP converting enzyme) and pro-ANP were measured in hospitalized patients with heart failure, using novel immunoassays. Patients (n = 14) had severe heart failure (NYHA class III-IV) with a median ejection fraction of 18 % and median BNP levels of 1940 pg/ml. In heart failure, median plasma corin levels were 7.6-fold lower than measured in plasma from 16 normal controls (180 vs. 1368 pg/ml, p<0.01). In contrast, in heart failure patients, levels of plasma N-terminal ANP peptides (N-ANP and pro-ANP) levels were markedly elevated (42.0 vs. 7.5 ng/ml, p<0.01). Levels of uncleaved pro-ANP, measured by novel immunoassays, were significantly higher in heart failure patients (p < 0.01) suggesting that corin cleavage of pro-ANP was impaired. Median plasma levels of cGMP were elevated in heart failure patients (150.0 vs. 7.6 pmol/ml, p<0.01) and plasma cGMP levels positively correlated with the fractional amount of cleaved pro-ANP (r(s) = 0.59, p < 0.03) but not with levels of uncleaved pro-ANP, implying that the cellular response to ANP remained intact. Conclusions: -Taken together these data suggest that there may be patients for whom low corin levels and impaired pro-ANP cleavage contribute to acute decompensation.

Circ Heart Fail: 10 Jan 2011; epub ahead of print
Ibebuogu UN, Gladysheva IP, Houng AK, Reed GL
Circ Heart Fail: 10 Jan 2011; epub ahead of print | PMID: 21216831
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Abstract

Chronic Kidney Disease and the Risk of Heart Failure in Men.

Dhingra R, Gaziano JM, Djoussé L
Background: -The relations between chronic kidney disease (CKD) and incident heart failure remain unclear. Methods and results: -We related CKD to incident nonfatal heart failure and cardiovascular (CVD) death (as separate and combined endpoints) in 10,181 male participants (mean age, 67 years). Kidney function was assessed by estimated glomerular filtration rate (eGFR) using Modification of Diet in Renal Disease equation in clinically relevant categories of <60 and ≥60 ml/min/1.73 m(2) (referent); and <45, 45 to 60, 60 to 90 and ≥90 ml/min/1.73 m(2) (referent). During follow up (mean 10.1 years; range 0.03-12.2), 439 developed heart failure and 832 had CVD death/heart failure. In multivariable models, men with eGFR <60ml/min/1.73 m(2) had a 2-fold risk of heart failure (95% confidence interval [CI], 1.62-2.56, p<0.0001) compared to referent category. The hazard ratio [HR] (with corresponding 95% CI) for development of heart failure according to eGFR categories of 60-90, 45-60, and <45ml/min/1.73 m(2) compared to referent category were 1.24 (0.98-1.56), 2.58 (1.91-3.49) and 1.52 (0.92-2.76) respectively. In the analyses restricted to subgroup of non-diabetics and normotensive individuals at baseline (n=7545), men with eGFR <60 ml/min/1.73 m(2) had 2.2-fold risk of heart failure (95% CI 1.66-2.95), compared to men with eGFR≥60 ml/min/1.73 m(2). Additionally, risk of heart failure or CVD death was >2.5-fold higher among individuals with eGFR 45-60 and <45 ml/min/1.73 m(2), compared to referent category. Conclusions: -Moderate level of CKD, even in absence of diabetes and hypertension at baseline, is associated with a higher risk of developing heart failure and CVD death/heart failure in men.

Circ Heart Fail: 10 Jan 2011; epub ahead of print
Dhingra R, Gaziano JM, Djoussé L
Circ Heart Fail: 10 Jan 2011; epub ahead of print | PMID: 21216838
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Abstract

A Simultaneous X-MRI and Non Contact Mapping Study of the Acute Hemodynamic Effect of Left Ventricular Endocardial and Epicardial Cardiac Resynchronization Therapy in Humans.

Ginks MR, Lambiase PD, Duckett SG, Bostock J, ... Razavi R, Rinaldi CA
Background: -Cardiac resynchronization therapy (CRT) utilising endocardial left ventricular (LV) pacing may be superior to conventional CRT. We studied the acute hemodynamic response (HR) to conventional CRT and LV pacing from different endocardial sites using a combined cardiac MRI and LV non-contact mapping protocol to gain insights into the underlying mechanisms. Methods and results: -Fifteen patients (63±10yrs, 12 male) awaiting CRT were studied in a combined X-Ray and MRI (XMR) laboratory. Delayed enhancement Cardiac MR (DE-CMR) was performed to define areas of myocardial fibrosis. Patients underwent an electrophysiological study incorporating endocardial and epicardial LV pacing. Acute HR was measured using a pressure wire within the LV cavity to derive LV dP/dt max. Non-contact mapping (NCM) was used to define areas of slow conduction. There was a significant improvement in all LV pacing modes versus baseline (p<0.001). LV endocardial CRT from the best endocardial site was superior to conventional CRT with a percentage change in dP/dt max of 79.8±49.0% vs. 59.6±49.5% from baseline (p < 0.05). The hemodynamic benefits of pacing were greater when LV stimulation was performed outside of areas of slow conduction defined by NCM. (p <0.001). DE-CMR was able to delineate zones of slow conduction seen with NCM in ischemic patients but was unreliable in non-ischemic patients. Conclusions: -Endocardial LV pacing appears superior to conventional CRT although the optimal site varies between subjects and is influenced by pacing within areas of slow conduction. DE-CMR was a poor predictor of zones of slow conduction in non-ischemic patients.

Circ Heart Fail: 10 Jan 2011; epub ahead of print
Ginks MR, Lambiase PD, Duckett SG, Bostock J, ... Razavi R, Rinaldi CA
Circ Heart Fail: 10 Jan 2011; epub ahead of print | PMID: 21216832
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Abstract

Effects of Continuous- Versus Pulsatile-Flow Left Ventricular Assist Devices on Myocardial Unloading and Remodeling.

Kato TS, Chokshi A, Singh P, Khawaja T, ... Mancini DM, Schulze PC
Background: -Continuous-flow left ventricular assist devices (LVAD) are increasingly used for patients with end-stage heart failure (HF). We analyzed the effects of ventricular decompression by continuous- versus pulsatile-flow LVADs on myocardial structure and function in this population. Methods and results: -Sixty-one patients who underwent LVAD implantation as bridge-to-transplant were analyzed (pulsatile-flow LVAD: Group P, n=31; continuous-flow LVAD: Group C, n=30). Serial echocardiograms, serum levels of brain natriuretic peptide (BNP) and extracellular matrix biomarkers (ECM) were compared between the groups. Myocardial BNP and ECM gene expression were evaluated in a subset of 18 patients. Postoperative left ventricular (LV) ejection fraction was greater (33.2±12.6 vs. 17.6±8.8%, p<0.0001) and the mitral E/E\' was lower (9.9±2.6 vs. 13.2±3.8, p=0.0002) in Group P versus Group C. Postoperative serum levels of BNP, metalloproteinases (MMP)-9 and tissue inhibitor of MMP (TIMP)-4 were significantly lower in Group P compared to Group C (BNP: 552.6±340.6 vs. 965.4±805.7 pg/mL, p<0.01; MMP9: 309.0±220.2 vs. 475.2±336.9 ng/dL, p<0.05; TIMP4: 1490.9±622.4 vs. 2014.3±452.4 ng/dL, p<0.001). Myocardial gene expression of ECM markers and BNP decreased in both groups; however, expression of TIMP-4 decreased only in Group P (p=0.024). Conclusions: -Mechanical unloading of the failing myocardium using pulsatile devices is more effective as indicated by echocardiographic parameters of systolic and diastolic LV function as well as dynamics of BNP and ECM markers. Therefore, specific effects of pulsatile mechanical unloading on the failing myocardium may have important implications for device selection especially for the purpose of bridge-to-recovery in patients with advanced HF.

Circ Heart Fail: 18 Jul 2011; epub ahead of print
Kato TS, Chokshi A, Singh P, Khawaja T, ... Mancini DM, Schulze PC
Circ Heart Fail: 18 Jul 2011; epub ahead of print | PMID: 21765125
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Abstract

Osteopontin Expression in Cardiomyocytes Induces Dilated Cardiomyopathy.

Renault MA, Robbesyn F, Réant P, Douin V, ... Charpentier F, Gadeau AP
Background: -Inflammatory processes play a critical role in myocarditis, dilated cardiomyopathy and heart failure. The expression of the inflammatory chemokine osteopontin (OPN) is dramatically increased in cardiomyocytes and inflammatory cells during myocarditis and heart failure in human and animals. However its role in the development of heart diseases is not known. Methods and results: -To understand whether OPN is involved in cardiomyopathies, we generated a transgenic mouse (MHC-OPN) that specifically overexpresses OPN in cardiomyocytes using cardiac specific promoter-directed OPN expression. Young MHC-OPN mice were phenotypically indistinguishable from their control littermates, but most of them died prematurely with a half life of 12 weeks of age. Electrocardiography revealed conduction defects. Echocardiography showed LV dilation and systolic dysfunction. Histological analysis revealed cardiomyocyte loss, severe fibrosis and inflammatory cell infiltration. Most of these inflammatory cells were activated T cells with Th1 polarization and cytotoxic activity. Autoantibodies against OPN, cardiac myosin or troponin I, were not found in the serum of MHC-OPN mice. Conclusions: -These data show that OPN expression in the heart induces in vivo, T cell recruitment and activation leading to chronic myocarditis, the consequence of which is myocyte destruction and hence, dilated cardiomyopathy. Thus, OPN might therefore constitute a potential therapeutic target to limit heart failure.

Circ Heart Fail: 04 Mar 2010; epub ahead of print
Renault MA, Robbesyn F, Réant P, Douin V, ... Charpentier F, Gadeau AP
Circ Heart Fail: 04 Mar 2010; epub ahead of print | PMID: 20200330
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Abstract

Predictors of Incident Heart Failure in a Large Insured Population: A One Million Person-Year Follow-up Study.

Goyal A, Norton CR, Thomas TN, Davis RL, ... Vaccarino V, Wilson PW
Background: -Studies on the incidence and predictors of heart failure (HF) are often restricted to elderly persons, or identify only inpatient cases. Methods and results: -We determined the incidence and predictors of new HF diagnosed in either outpatient or inpatient settings, among 359,947 women and men (age >/= 18 years) insured by Kaiser Permanente Georgia at any time during calendar years 2000-2005. Subjects were free of HF at baseline, and incident HF was identified with ICD-9 codes (one inpatient or two outpatient HF visits). We developed multivariable Cox models to assess the association of antecedent factors (coronary heart disease, hypertension, diabetes mellitus, atrial fibrillation, and valvular heart disease) with incident HF. Separate models were created for each sex, and for newly diagnosed HF in outpatient or inpatient settings. There were 4,001 incident HF cases (50% women, and 48% in subjects < 65 years old), during 1,015,794 person-years follow-up. The incidence rate of HF was greater in men than in women (4.24 versus 3.68 per 1,000 person-years), but was stable across the study interval in both sexes. Two-thirds of incident HF cases from this population occurred in outpatients. These five antecedent factors and age yielded excellent discrimination for incident HF in both outpatients and inpatients, and in both sexes (C>0.85 in all models). Conclusions: -Common, modifiable risk factors accurately discriminate women and men at risk for HF diagnosed in either outpatient or inpatient settings. Approximately two-thirds of new HF cases in our insured population were diagnosed in outpatients; more research is needed to characterize these subjects and their prognosis.

Circ Heart Fail: 27 Aug 2010; epub ahead of print
Goyal A, Norton CR, Thomas TN, Davis RL, ... Vaccarino V, Wilson PW
Circ Heart Fail: 27 Aug 2010; epub ahead of print | PMID: 20798277
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Abstract

Right Ventricular Failure in Idiopathic Pulmonary Arterial Hypertension Is Associated with Inefficient Myocardial Oxygen Utilization.

Wong YY, Ruiter G, Lubberink M, Raijmakers P, ... van der Laarse WJ, Vonk-Noordegraaf A
Background: -In idiopathic pulmonary arterial hypertension (IPAH), increased right ventricular (RV) power is required to maintain cardiac output. For this, RV O(2) consumption (MVO(2)) must increase by augmentation of O(2) supply and/or improvement of mechanical efficiency - ratio of power output to MVO(2). In IPAH with overt RV failure, however, there is evidence that O(2) supply (perfusion) reserve is reduced, leaving only increase in either O(2) extraction or mechanical efficiency as compensatory mechanisms. We related RV mechanical efficiency to clinical and hemodynamic parameters of RV function in IPAH patients and associated it with glucose metabolism. Methods and results: -The patients included were NYHA II (n=8) and III (n=8). They underwent right heart catheterisation, MRI and H(2)(15)O-, (15)O(2)-, C(15)O- and (18)FDG-PET. RV power and O(2) supply were similar in both groups (NYHA II vs III: 0.54±0.14 vs 0.47±0.12 J/s; and 0.109±0.022 vs 0.128±0.026 ml O(2)/min/g, respectively). RV O(2) extraction was near-significantly lower in NYHA II compared with NYHA III (63±17% vs 75±16%, respectively, P=0.10). As a result, MVO(2) was significantly lower (0.066±0.012 vs 0.092±0.010 ml O(2)/min/g, respectively, P=0.006). RV efficiency was reduced in NYHA III (13.9±3.8%) compared to NYHA II (27.8±7.6%, P=0.001). Septal bowing, measured by MRI, correlated with RV efficiency (r=-0.59, P=0.020). No relation was found between RV efficiency and glucose uptake rate. RV mechanical efficiency and ejection fraction were closely related (r=0.81, P<0.001). Conclusions: -RV failure in IPAH was associated with reduced mechanical efficiency that was partially explained by RV mechanical dysfunction, but not by a metabolic shift.

Circ Heart Fail: 08 Sep 2011; epub ahead of print
Wong YY, Ruiter G, Lubberink M, Raijmakers P, ... van der Laarse WJ, Vonk-Noordegraaf A
Circ Heart Fail: 08 Sep 2011; epub ahead of print | PMID: 21900188
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Abstract

Race, Gender, and Age Differences in Heart Failure-Related Hospitalizations in a Southern State: Implications for Prevention.

Husaini BA, Mensah GA, Sawyer D, Cain VA, ... Levine RS, Sampson UK
Background: -Since heart failure (HF) is the final common pathway for most heart diseases, we examined its 10-year prevalence trend by race, gender, and age in Tennessee. Methods and results: -HF hospitalization data from the Tennessee Hospital Discharge Data System were analyzed by race, gender and age. Rates were directly age-adjusted using the Year 2000 standard population. Adult (age 20+) in-patient hospitalization for primary diagnosis of HF (HFPD) increased from 4.2% in 1997 to 4.5% in 2006. Age-adjusted hospitalization for HF (per 10,000 population) rose by 11.3% (from 29.3 in 1997 to 32.6 in 2006). Parallel changes in secondary HF admissions were also noted. Age-adjusted rates were higher among blacks than whites and higher among men than women. The ratios of black to white by gender admitted with HFPD in 2006 were highest (9:1) among the youngest age categories (20-34 and 35-44 years). Furthermore, for each age category of black men below 65 years, there were higher HF admission rates than for white men in the immediate older age category. In 2006, the adjusted rate ratios for HFPD in black to white men aged 20-34 and 35-44 years were OR=4.75, CI (3.29-6.86) and OR 5.10, CI (4.15-6.25) respectively. Hypertension was the independent predictor of HF admissions in black men age 20-34 years. Conclusions: -The higher occurrence of HF among young adults in general, particularly among young black men, highlights the need for prevention by identifying modifiable biological and social determinants in order to reduce cardiovascular health disparities in this vulnerable group.

Circ Heart Fail: 23 Dec 2010; epub ahead of print
Husaini BA, Mensah GA, Sawyer D, Cain VA, ... Levine RS, Sampson UK
Circ Heart Fail: 23 Dec 2010; epub ahead of print | PMID: 21178017
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Abstract

Osteoprotegerin Predicts Progression of Chronic Heart Failure: Results from CORONA.

Ueland T, Dahl CP, Kjekshus J, Hulthe J, ... Aukrust P, Gullestad L
Background: -Osteoprotegerin (OPG) may be implicated in the pathogenesis of heart failure (HF) and circulating levels predict survival in patients with post-infarction HF. Our primary goal was to determine whether OPG provided independent prognostic information in patients with chronic HF, and to examine its potential interactions with statin therapy. Methods and results: -OPG as a risk factor for the primary endpoint (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke; n=318), all-cause mortality (n=329) and all-cause mortality/hospitalization for worsening of heart failure (WHF; n=475) was investigated in 1464 patients (≥ 60 years, NYHA class II-IV, ischaemic systolic HF, optimal pharmacological therapy) in the Controlled Rosuvastatin Multinational Trial in HF (CORONA) population, randomly assigned to 10 mg rosuvastatin or placebo. In multi-variable analyses, OPG (continuous variable) added no significant predictive information for risk estimation of the primary endpoint (adjusting for left ventricular ejection fraction, NYHA class, age, body mass index, diabetes, sex, intermittent claudication, heart rate, serum creatinine, apoA1 and NT-proBNP). However, OPG added independent predictive information for WHF hospitalization [HR 1.10 (1.04-1.16), p<0.001] and all-cause mortality/WHF hospitalization [HR 1.06 (1.01-1.11)]. The HR indicated a reduced risk for all-cause mortality in the rosuvastatin group in those with lowest OPG values (Tertile 1, HR=0.66 un-adjusted [p=0.025]; HR=0.71 Cox adjusted [p=0.025]; interaction by treatment effect for the Tertiles p=0.086). Conclusions: -OPG added no predictive information for the primary endpoint, but independently predict WHF hospitalization in older patients with advanced chronic systolic HF of ischemic aetiology. Clinical trial registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00206310.

Circ Heart Fail: 10 Jan 2011; epub ahead of print
Ueland T, Dahl CP, Kjekshus J, Hulthe J, ... Aukrust P, Gullestad L
Circ Heart Fail: 10 Jan 2011; epub ahead of print | PMID: 21216833
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Abstract

Resting Heart Rate and the Risk of Heart Failure in Healthy Adults: The Rotterdam Study.

Nanchen D, Leening MJ, Locatelli I, Cornuz J, ... Witteman JC, Dehghan A
Background: -An elevated resting heart rate is associated with re-hospitalization for heart failure and is a modifiable risk factor in heart failure patients. We aimed to examine the association between resting heart rate and incident heart failure in a population-based cohort study of healthy adults without pre-existing overt heart disease. Methods and results: -We studied 4,768 men and women aged 55 years or older from the population-based Rotterdam Study. We excluded participants with prevalent heart failure, coronary heart disease, pacemaker, atrial fibrillation, atrio-ventricular block, and those using beta-blockers or calcium channel blockers. We used extended Cox-models allowing for time-dependent variation of resting heart rate along follow-up. Over a median of 14.6 years of follow-up, 656 participants developed heart failure. The risk of heart failure was higher in men with higher resting heart rate. For each increment of 10 beats per minute, the multivariable adjusted hazard ratios in men were 1.16 (95% confidence interval [CI], 1.05-1.28, p=0.005) in the time-fixed heart rate model and 1.13 (95% CI 1.02-1.25, p=0.017) in the time-dependent heart rate model. The association could not be demonstrated in women (p for interaction = 0.004). Censoring participants for incident coronary heart disease, or using time-dependent models to account for the use of beta-blockers or calcium channel blockers during follow-up did not alter the results. Conclusions: -Baseline or persistent higher resting heart rate is an independent risk factor for the development of heart failure in healthy older men in the general population.

Circ Heart Fail: 18 Apr 2013; epub ahead of print
Nanchen D, Leening MJ, Locatelli I, Cornuz J, ... Witteman JC, Dehghan A
Circ Heart Fail: 18 Apr 2013; epub ahead of print | PMID: 23599310
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Abstract

Clinical Characteristics of Pulmonary Hypertension in Patients with Heart Failure and Preserved Ejection Fraction.

Thenappan T, Shah SJ, Gomberg-Maitland M, Collander B, ... Shroff P, Rich S
Background: -Pulmonary vascular disease associated with left-sided heart failure and preserved ejection fraction (PH-HFpEF) is an increasingly common cause of pulmonary hypertension. The distinction between PH-HFpEF and pulmonary arterial hypertension (PAH) is important, as therapies indicated for PAH can be detrimental in HFpEF. The characteristic features of PH-HFpEF are understudied. Methods and results: -In a cross-sectional study, we compared the clinical, echocardiographic and hemodynamic features of PH-HFpEF (N=100), with PAH (N = 522), and HFpEF without pulmonary vascular disease (N = 45). We determined the clinical characteristics that best differentiated PH-HFpEF from PAH. Compared to patients with PAH, patients with PH-HFpEF were older; had a higher prevalence of cardiovascular comorbidities; had worse exercise capacity and renal function; more frequently had left atrial enlargement; and less frequently had right atrial enlargement. PH was less severe in PH-HFpEF patients than in PAH patients (pulmonary vascular resistance 4.8 (IQR 3-8.4) vs. 10.9 (IQR 7.4-15.7) Wood units; P<0.001]. Old age, presence of hypertension and coronary artery disease, absence of right atrial enlargement, higher aortic systolic pressure, higher mean right atrial pressure, and higher cardiac output best differentiated PH-HFpEF from PAH (area under the ROC curve 0.97). Compared to HFpEF patients without pulmonary hypertension, PH-HFpEF patients were often female and more symptomatic; more often had right ventricular hypertrophy and right atrial enlargement; and had higher right atrial pressure. Conclusions: -These data should help better identify PH-HFpEF, an entity that has become increasingly recognized and difficult to treat.

Circ Heart Fail: 17 Mar 2011; epub ahead of print
Thenappan T, Shah SJ, Gomberg-Maitland M, Collander B, ... Shroff P, Rich S
Circ Heart Fail: 17 Mar 2011; epub ahead of print | PMID: 21411741
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Abstract

Ethnic Differences in Macrovascular and Microvascular Function in Systolic Heart Failure.

Shantsila E, Wrigley B, Shantsila A, Tapp LD, ... Gill PS, Lip GY
Background: -Endothelial dysfunction is implicated in the pathophysiology of heart failure (HF), and ethnic differences in the presentation of cardiovascular disease are evident, with an excess seen amongst South Asians (SAs). However, data on ethnic differences in endothelial function in HF are limited. Methods and results: -In a cross-sectional study we recruited 128 subjects with systolic HF: 50 SAs, 50 Whites, and 28 African-Caribbeans (ACs). Additionally, SAs with systolic HF were compared to 40 SAs with CAD without HF (\'disease controls\', DC) and 40 SA healthy controls (HC). Macrovascular endothelial function was assessed by measurement of flow-mediated dilation (FMD) in response to hyperaemia, arterial stiffness was assessed by the pulse wave velocity (PWV),and microvascular endothelial function by forearm laser Doppler flowmetry. CD144-expressing endothelial microparticles were measured by flow cytometry. When compared to DC and HC, SAs with HF had impaired microvascular response to acetylcholine (p=0.001) and reduced FMD (p<0.001). In comparing ethnic groups, SAs with HF had impaired response to acetylcholine (123±95.5%) compared to WEs (258±156%) and ACs (286±173%, p<0.001 for both). Whites had higher FMD (8.49±4.63%) than SAs (4.76±4.78%, p<0.001) and ACs (4.55±3.56%, p=0.01). No difference in endothelial-independent response was observed between study groups, nor in PWV. Ethnicity remained associated with microvascular endothelial function even after adjustment for age, presence of hypertension and diabetes, blood pressure and glucose levels (p=0.003). There were not differences in numbers of endothelial microparticles. Conclusions: -SAs with HF have impaired micro- and macro-vascular endothelial function, but preserved arterial elastic properties. Significant ethnic differences in endothelial function are evident in subjects with HF, with ethnicity being associated with microvascular endothelial dysfunction in this disorder.

Circ Heart Fail: 14 Sep 2011; epub ahead of print
Shantsila E, Wrigley B, Shantsila A, Tapp LD, ... Gill PS, Lip GY
Circ Heart Fail: 14 Sep 2011; epub ahead of print | PMID: 21914813
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Abstract

Sildenafil Preserves Lung Endothelial Function and Prevents Pulmonary Vascular Remodeling in a Rat Model of Diastolic Heart Failure.

Yin J, Kukucka M, Hoffmann J, Sterner-Kock A, ... Kuppe H, Kuebler WM
Background: -Pulmonary hypertension as frequent complication of left heart disease (PH-LHD) is characterized by lung endothelial dysfunction and vascular remodeling. While PH-LHD contributes to morbidity and mortality in heart failure, established therapies for PH-LHD are yet lacking. Here, we tested the effect of chronic sildenafil treatment in an experimental model of PH-LHD. Methods and results: -In Sprague-Dawley rats, PH-LHD was induced by supracoronary aortic banding. Oral sildenafil treatment (60 mg/kg daily) was initiated after 7 days, and lung endothelial function (n=5), vascular remodeling, and right ventricular function (n=11 each) were analyzed 9 weeks post banding. As compared to sham-operated controls, aortic banding induced pulmonary hypertension and lung endothelial dysfunction evident as lack of endothelial NO production and endothelium-dependent vasodilation. These changes were associated with an increased pulmonary vascular resistance, medial thickening, and biventricular cardiac hypertrophy. Sildenafil treatment largely attenuated these pathologic changes, and was not associated with detectable adverse effects pertinent to lung vascular barrier function, edema formation, or systemic hemodynamics. Conclusions: -Our data identify sildenafil as a promising therapy for PH-LHD. In light of its documented protective effects at the myocardial level in heart failure, sildenafil presents a particularly attractive strategy in that it simultaneously targets cardiac remodeling and secondary PH-LHD.

Circ Heart Fail: 10 Jan 2011; epub ahead of print
Yin J, Kukucka M, Hoffmann J, Sterner-Kock A, ... Kuppe H, Kuebler WM
Circ Heart Fail: 10 Jan 2011; epub ahead of print | PMID: 21216837
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Abstract

Physical Fitness and Risk for Heart Failure and Coronary Artery Disease.

Berry JD, Pandey A, Gao A, Leonard D, ... Defina L, Willis B
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.

Circ Heart Fail: 15 May 2013; epub ahead of print
Berry JD, Pandey A, Gao A, Leonard D, ... Defina L, Willis B
Circ Heart Fail: 15 May 2013; epub ahead of print | PMID: 23677924
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Abstract

Lifestyle Factors in Relation to Heart Failure among Finnish Men and Women.

Wang Y, Tuomilehto J, Jousilahti P, Antikainen R, ... Katzmarzyk PT, Hu G
Background: -The role of lifestyle factors in explaining the risk of heart failure (HF) is not properly established. Methods and results: -The national population-based study included 18,346 Finnish men and 19,729 women who were 25 to 74 years of age and free of HF at baseline. Multivariable Cox proportional hazards regression models was used to examine the association between lifestyle factors (smoking, body mass index [BMI], physical activity, vegetable consumption, fruit consumption and alcohol consumption) and HF risk. During a median follow-up of 14.1 years (interquartile range 5.9-20.9 years), 638 men and 445 women developed HF. Fruit consumption and alcohol consumption were dropped out of the analyses because no significant associations with the risk of HF were found. When four modifiable lifestyle factors (smoking, BMI, physical activity, and vegetable intake) were included in the analysis, the multivariable-adjusted (age, education, systolic blood pressure, total cholesterol, and histories of myocardial infarction, valvular heart disease, diabetes and using anti-hypertensive drugs) hazard ratios (HRs) of HF associated with engaging in 0, 1, 2, 3, and 4 healthy lifestyle factors were 1.00, 0.69 (95% confidence interval [CI] 0.54-0.87), 0.45 (95% CI 0.35-0.58), 0.34 (95% CI 0.25-0.46), and 0.31 (95% CI 0.17-0.56) (P<0.001 for trend) for men, and 1.00, 0.53 (95% CI 0.33-0.85), 0.42 (95% CI 0.26-0.67), 0.24 (95% CI 0.14-0.39), and 0.19 (95% CI 0.09-0.40) (P<0.001 for trend) for women, respectively. Conclusions: -The present study demonstrates an inverse association between healthy lifestyle patterns and the risk of HF in both Finnish men and women.

Circ Heart Fail: 14 Sep 2011; epub ahead of print
Wang Y, Tuomilehto J, Jousilahti P, Antikainen R, ... Katzmarzyk PT, Hu G
Circ Heart Fail: 14 Sep 2011; epub ahead of print | PMID: 21914814
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Abstract

Prognostic Value of Baseline Plasma Amino-Terminal Pro-Brain Natriuretic Peptide and its Interactions With Irbesartan Treatment Effects in Patients With Heart Failure and Preserved Ejection Fraction: Findings from the I-PRESERVE Trial.

Anand IS, Rector TS, Cleland JG, Kuskowski M, ... Massie B, Carson PE
Background: -Plasma concentrations of natriuretic peptides (NP) are associated with morbidity and mortality (M&M) in patients with systolic heart failure (HF). However, the role of NP as a prognostic marker in patients with HF and preserved ejection fraction (HFpEF) has not been studied in a large cohort of well characterized patients. Moreover, it is unclear whether treatments have a differential effect on M&M across the spectrum of NP levels. Methods and results: -NT-proBNP was measured at baseline in 3,480 patients in the Irbesartan in Heart Failure with Preserved Ejection Fraction Trial (I-PRESERVE). In a multi-variable Cox regression model, NT-proBNP above the median of 339 pg/mL was independently associated with an increased risk of the primary endpoint of all cause mortality and pre-specified cardiovascular hospitalizations (adjusted HR, 1.79; 95% CI, 1.56 to 2.10; P<0.001), all-cause mortality (adjusted HR, 2.04; 95% CI, 1.682.0 to 2.47; P<0.001) and a composite of HF events, including death due to worsening HF or sudden death or hospitalization due to worsening HF (adjusted HR, 1.77; 95% CI, 1.43 to 2.20; P<0.001). There were significant interactions between the effect of irbesartan and median split of baseline NT-proBNP for the primary outcome (P=0.005), all-cause mortality (P=0.05) and the HF composite outcome (p<0.001). Use of irbesartan was associated with improved outcomes in patients with NT-proBNP below but not above the median. After adjusting for 20 baseline covariates, irbesartan still had a beneficial effect on the primary outcome (HR 0.74; 95% CI 0.60 to 90; p=0.003), all-cause mortality (HR 0.75; 95% CI 0.56 to 0.99; p=0.046) and HF composite outcome (HR 0.57; 95% CI 0.41 to 0.80; p=0.001) in patients with NT-proBNP below median. Conclusions: -The unexpected benefit of irbesartan in lower risk HFpEF patients in this post-hoc analysis may indicate effects on early, but not later high-risk stages of the disease. These findings question the strategy of using elevated plasma concentrations of natriuretic peptides as a patient selection criterion in HFpEF trials. More studies are needed to support or contest this practice. Clinical trial registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.

Circ Heart Fail: 30 Jun 2011; epub ahead of print
Anand IS, Rector TS, Cleland JG, Kuskowski M, ... Massie B, Carson PE
Circ Heart Fail: 30 Jun 2011; epub ahead of print | PMID: 21715583
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Abstract

Impact of the Length of Vitamin D Deficiency on Cardiac Remodeling.

Assalin HB, Rafacho BP, Dos Santos PP, Ardisson LP, ... Zornoff LA, Rupp de Paiva SA
Background: -This study was aimed to evaluate the influence of vitamin D (VD) deficiency on cardiac metabolism, morphology and function. Thus, we investigated the relationship of these changes with the length of the nutrient restriction. Methods and results: -Male weanling Wistar rats were allocated into four groups: C2(n=24), animals were fed an AIN-93G diet with 1,000 IU VD/kg of chow and were kept under fluorescent light for 2 months; D2(n=22), animals were fed a VD - deficient AIN-93G diet and were kept under incandescent light for 2 months; C4(n=21) animals were kept in the same conditions of C2 for 4 months; D4(n=23) animals were kept in the same conditions of D2 for 4 months. Biochemical analyses showed lower beta-hydroxyacyl coenzyme-A dehydrogenase activity and higher lactate dehydrogenase (LDH) activity in VD deficient animals. Furthermore, VD deficiency was related to increased cytokines release, oxidative stress, apoptosis and fibrosis. Echocardiographic data showed left ventricular (LV) hypertrophy and lower fractional shortening and ejection fraction in VD deficient animals. Difference became evident in the LDH activity, LV weight, right ventricle weight, and LV mass after 4 months of VD deficiency. Conclusions: -Our data indicate that VD deficiency is associated to energetic metabolic changes, cardiac inflammation, oxidative stress, fibrosis and apoptosis, cardiac hypertrophy, left chambers alterations and systolic dysfunction. Furthermore, length of the restriction influenced these cardiac changes.

Circ Heart Fail: 26 May 2013; epub ahead of print
Assalin HB, Rafacho BP, Dos Santos PP, Ardisson LP, ... Zornoff LA, Rupp de Paiva SA
Circ Heart Fail: 26 May 2013; epub ahead of print | PMID: 23709660
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Abstract

Modulation of Novel Cardiorenal and Inflammatory Biomarkers by Intravenous Nitroglycerin and Nesiritide in Acute Decompensated Heart Failure: An Exploratory Study.

Chow SL, O\'Barr SA, Peng J, Chew E, ... Patterson JH, Heywood JT
Background: -Modulation of novel cardiorenal and inflammatory markers may provide insight into disease process and outcome of patients with acute decompensated heart failure (ADHF). Methods and results: -In this open-labeled prospective randomized study, 89 patients received either nesiritide (NES) or nitroglycerin (NTG) infusion by standard protocol. The serum or plasma concentrations of cystatin-C, and inflammatory markers: high sensitivity C-reactive protein (hsCRP), tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β), and inteleukin-6 (IL-6), were measured in 66 patients with ADHF at baseline and during drug infusion. Mean baseline values for demographics were not significantly different between NTG and NES groups; however, baseline inflammatory markers were elevated on admission. In NES compared to NTG groups, lower cystatin-C (1449 vs. 2739 ng/mL, p<0.05) and IL-6 (25 vs. 50 pg/mL, p<0.05) were observed. There were no significant differences in concentrations of hsCRP, TNF-α, and TGF-β between groups over time. Conclusions: -The differential modulation effects of cystatin-C and IL-6, but not other inflammatory markers, in response to nesiritide compared to nitroglycerin therapy may provide important implications for vasodilator therapy. Further studies are warranted to confirm these findings. Clinical trial registration-URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00842023.

Circ Heart Fail: 17 May 2011; epub ahead of print
Chow SL, O'Barr SA, Peng J, Chew E, ... Patterson JH, Heywood JT
Circ Heart Fail: 17 May 2011; epub ahead of print | PMID: 21576282
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Abstract

Plasma Soluble Corin in Patients with Heart Failure.

Dong N, Chen S, Yang J, He L, ... Plow E, Wu Q
Background: -Corin is a transmembrane protease that processes natriuretic peptides in the heart. Like many membrane proteins, corin is shed from the cell surface. Methods and results: -In this study, we obtained plasma samples from healthy controls and patients with heart failure (HF) and acute myocardial infarction (AMI). Soluble corin levels in plasma were measured by an ELISA method. In healthy adults (n=198), plasma corin levels were 690 (SD 260) pg/mL. The corin levels did not differ significantly among different age groups. In patients with HF (n=291), plasma corin levels were significantly lower compared to that of healthy controls (365 (SD 259) pg/mL, p<0.001). The reduction in plasma corin levels appeared to correlate with the severity of HF. In patients of New York Heart Association (NYHA) classes II, III and IV, plasma corin levels were 450 (SD 281) (n=69), 377 (SD 270) (n=132), and 282 (SD 194) (n=90) pg/mL, respectively (p<0.001 class II vs. IV; p<0.05 class III vs. IV). In contrast, plasma corin levels in patients with AMI (n=73) were similar to that of healthy controls (678 (SD 285) pg/mL, p>0.05). Conclusions: -Soluble corin was detected in human plasma. Plasma corin levels were reduced significantly in patients with HF but not AMI. Our results indicate that corin deficiency may contribute to the pathogenesis of HF and that plasma corin may be used as a biomarker in the diagnosis of HF.

Circ Heart Fail: 11 Jan 2010; epub ahead of print
Dong N, Chen S, Yang J, He L, ... Plow E, Wu Q
Circ Heart Fail: 11 Jan 2010; epub ahead of print | PMID: 20061521
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Abstract

Coenzyme Q10 and Heart Failure: A State-of-the-Art Review.

Sharma A, Fonarow GC, Butler J, Ezekowitz JA, Felker GM
Heart failure (HF) with either preserved or reduced ejection fraction is associated with increased morbidity and mortality. Evidence-based therapies are often limited by tolerability, hypotension, electrolyte disturbances, and renal dysfunction. Coenzyme Q10 (CoQ10) may represent a safe therapeutic option for patients with HF. CoQ10 is a highly lipophilic molecule with a chemical structure similar to vitamin K. Although being a common component of cellular membranes, CoQ10\'s most prominent role is to facilitate the production of adenosine triphosphate in the mitochondria by participating in redox reactions within the electron transport chain. Numerous trials during the past 30 years examining CoQ10 in patients with HF have been limited by small numbers and lack of contemporary HF therapies. The recent publication of the Q-SYMBIO randomized controlled trial demonstrated a reduction in major adverse cardiovascular events with CoQ10 supplementation in a contemporary HF population. Although having limitations, this study has renewed interest in evaluating CoQ10 supplementation in patients with HF. Current literature suggests that CoQ10 is relatively safe with few drug interactions and side effects. Furthermore, it is already widely available as an over-the-counter supplement. These findings warrant future adequately powered randomized controlled trials of CoQ10 supplementation in patients with HF. This state-of-the-art review summarizes the literature about the mechanisms, clinical data, and safety profile of CoQ10 supplementation in patients with HF.

Circ Heart Fail: 24 Mar 2016; 9:e002639
Sharma A, Fonarow GC, Butler J, Ezekowitz JA, Felker GM
Circ Heart Fail: 24 Mar 2016; 9:e002639 | PMID: 27012265
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Abstract

Angiotensin II Converting Enzyme Inhibition Improves Survival, Ventricular Remodeling and Myocardial Energetics in Experimental Aortic Regurgitation.

Arsenault M, Zendaoui A, Roussel E, Drolet MC, ... Lecomte R, Couet J
-Aortic valve regurgitation (AR) is a volume overload disease causing severe eccentric left ventricular hypertrophy and eventually heart failure. There is currently no approved drug to treat patients with AR. Many vasodilators including angiotensin converting enzyme inhibitors have been evaluated in clinical trials but while some results were promising, others were inconclusive. Overall, no drug has yet been able to improve clinical outcome in AR and the controversy remains. We have previously shown in an animal model that captopril reduced left ventricular hypertrophy and protected LV systolic function but we had not evaluated the clinical outcome. This protocol was designed to evaluate the effects of a long term captopril treatment on survival in the same animal model of severe aortic valve regurgitation.

Circ Heart Fail: 16 Jul 2013; epub ahead of print
Arsenault M, Zendaoui A, Roussel E, Drolet MC, ... Lecomte R, Couet J
Circ Heart Fail: 16 Jul 2013; epub ahead of print | PMID: 23861486
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Abstract

Hyponatremia, Natriuretic Peptides and Outcomes in Acutely Destabilized Heart Failure: Results from the International Collaborative of NT-proBNP (ICON) Study.

Mohammed AA, van Kimmenade RR, Richards M, Bayes-Genis A, ... Moore SA, Januzzi JL
Background: -Hyponatremia is a well-known predictor of mortality in patients with acutely decompensated heart failure (ADHF). Associations between hyponatremia and other prognostic variables in ADHF, such as amino-terminal pro-B type natriuretic peptide remain unclear. Methods and results: -628 patients presenting to the emergency department with ADHF were studied. All were hospitalized. Serum sodium (Na) concentration at presentation was examined as a function of mortality at one year, alone and relative to other predictors of death. Hyponatremia (Na </=135 mmol/L) was diagnosed in 24% (n=149) patients. Compared to those without hyponatremia, those affected were less likely to be male or to have hypertension or coronary artery disease, but were more likely to have severe symptoms, to be anemic, and to have higher NT-proBNP concentrations (all P </=0.05). When examined as a function of Na deciles (ranging from Na <132 mmol/L to Na >/=142 mmol/L), a U-shaped association was found between Na level and 1-year mortality. In multivariate Cox proportional hazards analysis, hyponatremia was an independent predictor of 1-year mortality (HR=1.72; 95% CI=1.22-2.37; P = 0.001) as was an NT-proBNP concentration above the median value of 4690 pg/mL (HR=1.49; 95% CI=1.10-2.00; P = 0.009). Those with hyponatremia and more elevated NT-proBNP were more likely to develop worsening renal function during their hospitalization and had highest rates of one-year death. Notably however, hyponatremia only predicted 1-year mortality in those with an elevated NT-proBNP. Conclusions: -Hyponatremia is associated with adverse outcome in patients with ADHF, however the prognostic value of low Na is mainly evident in those with more pronounced elevation of NT-proBNP concentrations.

Circ Heart Fail: 24 Mar 2010; epub ahead of print
Mohammed AA, van Kimmenade RR, Richards M, Bayes-Genis A, ... Moore SA, Januzzi JL
Circ Heart Fail: 24 Mar 2010; epub ahead of print | PMID: 20332419
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Abstract

Efficacy and Safety of Rivaroxaban in Patients with Heart Failure and Non-Valvular Atrial Fibrillation: Insights from ROCKET AF.

van Diepen S, Hellkamp AS, Patel MR, Becker RC, ... Fox KA, Mahaffey KW
Background: -In ROCKET AF, rivaroxaban was non-inferior to warfarin for the prevention of stroke and systemic embolic events and significantly reduced intracranial bleeding in patients with non-valvular atrial fibrillation (AF). We explore the safety and efficacy of rivaroxaban in patients with heart failure (HF). Methods and results: -A total of 9033 (63.7%) patients had HF. The primary efficacy analysis was rates of stroke or systemic embolism (per 100 patient years) by intention to treat. The safety outcomes were major or non-major clinically relevant (NMCR) bleeding and hemorrhagic stroke during treatment. Patients with HF were younger (72 vs. 74 years), more likely to have persistent AF (83.0% vs. 77.6%), and had higher mean CHADS2 scores (3.7 vs. 3.1). The efficacy of rivaroxaban compared with warfarin was similar in patients with HF (1.90 vs. 2.09) and without HF (2.10 vs. 2.54; p-interaction=0.62). The risk of major or NMCR bleeding with rivaroxaban was similar to warfarin in patients with HF (14.22 vs. 14.02) and without HF (16.12 vs. 15.35; p-interaction=0.99). A reduction in hemorrhagic stroke was observed with rivaroxaban in HF patients as in the overall trial (adjusted hazard ratio 0.38: 95% CI 0.19-0.76, p-interaction=0.067). Among patients with HF, the efficacy of rivaroxaban was similar irrespective of ejection fraction <40 or ≥40% (p-interaction=0.38), New York Heart Association class I-II vs. III-IV (p-interaction=0.68), HF preserved or reduced EF (p-interaction=0.35), or CHADS2 score 2 vs. ≥3 (p-interaction=0.48). Conclusions: -Treatment related outcomes were similar in patients with and without HF and across HF subgroups. These findings support the use of rivaroxaban as an alternative to warfarin in patients with AF and HF. Clinical trial registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

Circ Heart Fail: 30 May 2013; epub ahead of print
van Diepen S, Hellkamp AS, Patel MR, Becker RC, ... Fox KA, Mahaffey KW
Circ Heart Fail: 30 May 2013; epub ahead of print | PMID: 23723250
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Abstract

FGF23 Modifies the Relationship between Vitamin D and Cardiac Remodeling.

Ky B, Shults J, Keane MG, St John Sutton M, ... Sulik MJ, Leonard MB
Background: -There is growing evidence to support an important role for vitamin D and related hormones PTH and FGF23 on cardiac remodeling in chronic kidney disease (CKD). Our objective was to determine the relationships between vitamin D and cardiac remodeling in CKD and the effects of PTH and FGF23 on these associations. Methods and results: -In 1,431 participants from the Chronic Renal Insufficiency Cohort (CRIC) study, we measured 25(OH)D, 1,25(OH)2D, FGF23, and PTH, and performed quantitative echocardiography. Using linear regression methods, we determined significant negative interactions between 25(OH)D and FGF23 on LV mass (p=0.016); end-diastolic ([EDV], p=0.029); and end-systolic volumes ([ESV], p=0.021). In participants with an FGF23 level >the median of 123.5RU/ml, each doubling of 25(OH)D was associated with a 2.5% (95%CI -4.8,-0.2) lower LV mass. This association was less pronounced with FGF23 levels <the median (0.4%, 95%CI -1.9,2.7). Conversely, in participants with deficient 25(OH)D levels <20ng/ml, each doubling of FGF23 was associated with a 3.4% (95%CI 1.2,5.6) greater LV mass compared to only a 1.6% (95%CI -0.2,3.5) difference in participants with sufficient 25(OH)D. Similar findings were observed with 25(OH)D and volumes (p<0.05), and 1,25(OH)2D and LV mass and volumes (p<0.005). There was no effect modification by PTH. Conclusions: -We identified significant interactions between 25(OH)D, 1,25(OH)2D, and FGF23 on cardiac remodeling. Increased LV mass and cavity dilatation were observed with low 25(OH)D and high FGF23. Our findings suggest that consideration of both hormones is crucial to understanding the role of either in cardiac remodeling, and may have important therapeutic implications.

Circ Heart Fail: 09 Jun 2013; epub ahead of print
Ky B, Shults J, Keane MG, St John Sutton M, ... Sulik MJ, Leonard MB
Circ Heart Fail: 09 Jun 2013; epub ahead of print | PMID: 23748358
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Abstract

BNP Levels Predict Outcome in Pediatric Heart Failure Patients: Post-hoc Analysis of the Pediatric Carvedilol Trial.

Auerbach SR, Richmond ME, Lamour JM, Blume ED, ... Pahl E, Hsu DT
Background: -The ability of serum B-type natriuretic peptide levels (BNP) to predict outcomes in children with heart failure (HF) has not been well demonstrated. This study was designed to determine if BNP levels predict outcomes in patients with moderate symptomatic HF. Methods and results: -We investigated whether enrollment BNP levels for the Pediatric Carvedilol Trial were associated with baseline characteristics. Freedom from a composite endpoint of HF hospitalization, death, or transplantation at 9 months was compared using a threshold BNP level identified using receiver operating curve analysis. Median BNP level was 110 pg/ml (Interquartile range [IQR], 22.4 to 342.0 pg/ml) in 138 subjects. Median age was 3.4 years (IQR 1.1-11.0 years). Diagnoses were cardiomyopathy (60%) and congenital heart disease (40%); 73% had a systemic left ventricle (LV). BNP levels correlated moderately with LV ejection fraction (R=0.39, p<0.001), but did not differ by HF class, age, diagnosis, sex, ventricular morphology, or LV end-diastolic dimension Z-score (R=0.19). Outcome events included 25 HF hospitalizations, 4 deaths and 2 transplants. Sensitivity was 71% and specificity 63% for a BNP cutoff value of 140 pg/ml. BNP >/= 140 pg/ml (Hazard Ratio (HR) 3.7, CI 1.62-8.4, p=0.002) and age > 2 yr (HR 4.45, CI 1.68-12.04, p=0.003) were independently associated with worse outcomes. Conclusions: -In children with moderately symptomatic HF, BNP >/= 140 pg/ml and age > 2 yr identified subjects at higher risk for worse outcome. Further validation is needed to determine the BNP levels necessary to stratify risk in other pediatric cohorts.

Circ Heart Fail: 24 Jun 2010; epub ahead of print
Auerbach SR, Richmond ME, Lamour JM, Blume ED, ... Pahl E, Hsu DT
Circ Heart Fail: 24 Jun 2010; epub ahead of print | PMID: 20573993
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Abstract

Follistatin-like 1 in Chronic Systolic Heart Failure: A Marker of Left Ventricular Remodeling.

El-Armouche A, Ouchi N, Tanaka K, Doros G, ... Walsh K, Sam F
Background: -Follistatin-like 1 (FSTL1) is an extracellular glycoprotein that is found in human serum. Recent work suggests that FSTL1 is secreted in response to ischemic injuries and that its overexpression is protective in the heart and vasculature. Methods and results: -Here, we examined serum FSTL1 levels in patients with chronic heart failure with left ventricular (LV) ejection fraction <40% (n=86). The distribution of the sample, from these chronic heart failure patients, was separated into three tertiles of low, medium and high FSTL1 levels. Serum FSTL1 levels were increased 56% above age- and gender-matched, healthy controls. Diabetes mellitus, brain natriuretic peptide level, left atrial size, LV posterior wall thickness, LV end-diastolic diameter and LV mass were significant determinants of FSTL1 serum levels by bivariate analysis. After controlling for significant covariates, FSTL1 levels predicted LV hypertrophy (as measured by LV mass index) by multivariate linear regression analysis (P<0.001). Unadjusted survival analysis demonstrated increased mortality in patients with increasing FSTL1 levels (P=0.09). After adjusting for significant parameters, patients with increased FSTL1 remained at the highest risk of death [hazard ratio (95% confidence limits) 1.028, (0.98 and 1.78)]; (P=0.26). To determine whether elevated FSTL1 may be derived from the myocardium, FSTL1 protein expression was measured in samples from explanted, failing (n=18) and non-failing human hearts (n=7). LV failing hearts showed 2.5-fold higher FSTL1 protein levels than non-failing control hearts (P<0.05). Conclusions: -Elevated serum FSTL1 in human heart failure patients was associated with LV hypertrophy. Further studies on the role of FSTL1 as a biomarker in chronic systolic heart failure are warranted.

Circ Heart Fail: 30 May 2011; epub ahead of print
El-Armouche A, Ouchi N, Tanaka K, Doros G, ... Walsh K, Sam F
Circ Heart Fail: 30 May 2011; epub ahead of print | PMID: 21622850
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Abstract

Physical Health Status Measures Predict All-Cause Mortality in Heart Failure Patients.

Chamberlain AM, McNallan SM, Dunlay SM, Spertus JA, ... Weston SA, Roger VL
Background: -Physical health status measures have been shown to predict death in heart failure (HF); however, few studies found significant associations after adjustment for confounders and most were not representative of all HF patients. Methods and results: -HF patients from southeastern Minnesota were prospectively enrolled between 10/2007 and 12/2010, completed a 12-item Short Form Health Survey (SF-12) and a 6-minute walk, and were followed through 2011 for death from any cause. Scores ≤25 on the SF-12 physical component indicated low self-reported physical functioning, and the first question of the SF-12 measured self-rated general health. Low functional exercise capacity was defined as ≤300 meters walked during a 6 minute walk. Over a mean follow-up of 2.3 years, 86 deaths occurred among the 352 participants. A 1.6-fold (95% CI 1.0-2.7) and 1.8-fold (95% CI 1.1-2.9) increased risk of death was observed among patients with low self-reported physical functioning and low functional exercise capacity, respectively. Poor self-rated general health corresponded to a 2.7-fold (95% CI 1.5-4.9) increased risk of death compared to good-excellent general health. All measures equally discriminated between who would die and who would survive (C-statistics: 0.729, 0.750, and 0.740 for self-reported physical functioning, self-rated general health, and functional exercise capacity, respectively). Conclusions: -Three physical health status measures, captured by the SF-12 and a 6 minute walk, equally predict death among community HF patients. Therefore, the first question of the SF-12, which is the least burdensome to administer, may be sufficient to identify HF patients at greatest risk of death.

Circ Heart Fail: 28 Apr 2013; epub ahead of print
Chamberlain AM, McNallan SM, Dunlay SM, Spertus JA, ... Weston SA, Roger VL
Circ Heart Fail: 28 Apr 2013; epub ahead of print | PMID: 23625946
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Abstract

Interactions of enhanced urocortin 2 and mineralocorticoid receptor antagonism in experimental heart failure.

Rademaker MT, Charles CJ, Nicholls MG, Richards AM
Background: -Mineralocorticoid receptor antagonists (MRAs) have become established therapy in heart failure (HF). Urocortin 2 (Ucn2) is a novel peptide with potential in the treatment of this disease. The present study investigated the interactions of acute administration of Ucn2 and an MRA in experimental HF. Methods and results: -Ucn2 and an MRA (canrenoic acid (CA)) were infused for 4hours, both singly and together, in eight sheep with pacing-induced HF. Ucn2, when administered as an adjunct to CA, further improved hemodynamic indices relative to that achieved by CA alone, producing additional increases in cardiac output and decreases in left atrial pressure and peripheral resistance, but without eliciting a supplementary reduction in arterial pressure. Ucn2 co-treatment reversed CA-induced rises in circulating aldosterone levels, and also significantly reduced plasma renin activity, angiotensin II and vasopressin concentrations. While both CA and Ucn2 infusion produced a diuresis and natriuresis, responses with Ucn2 and Ucn+CA were 2-3-fold greater than that elicited by separate CA. Ucn2 co-therapy additionally increased urine potassium and creatinine excretion. In contrast to the rise in plasma potassium induced by CA, Ucn2 co-treatment reduced potassium concentrations. Conclusions: -Ucn2 co-treatment with an MRA in HF further improved hemodynamics relative to that achieved by CA alone, whilst also reducing plasma renin activity, angiotensin II, aldosterone and vasopressin levels, and enhancing renal function. Importantly, Ucn2 prevented CA-induced rises in plasma potassium. These data demonstrate a favorable profile of effects with short-term adjunct Ucn2 therapy and an MRA in HF.

Circ Heart Fail: 10 Jun 2013; epub ahead of print
Rademaker MT, Charles CJ, Nicholls MG, Richards AM
Circ Heart Fail: 10 Jun 2013; epub ahead of print | PMID: 23753530
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Abstract

Impact of Change in Serum Sodium Concentration on Mortality in Patients Hospitalized with Heart Failure and Hyponatremia.

Madan VD, Novak E, Rich MW
Background: -Hyponatremia is a common electrolyte abnormality among patients hospitalized with heart failure and it is a marker for increased short-term and long-term mortality. However, little is known about the time-course of hyponatremia and whether changes in serum sodium levels impact clinical outcomes. Methods and results: -322 patients hospitalized with decompensated heart failure and serum sodium <135 mmol/L were evaluated. Following hospital discharge, the first sodium value obtained within a 60-270 day period was recorded, and patients were classified into 3 groups based on whether the serum sodium value increased (≥2 mmol/L), decreased (≤2 mmol/L), or remained unchanged (±1 mmol/L) relative to the baseline value. Kaplan-Meier survival curves were constructed to illustrate mortality as a function of change in sodium concentration over time, and a Cox-proportional hazards model was constructed to determine if change in serum sodium concentration predicted mortality after adjusting for relevant covariates. The mean age of the population was 66 years, 45% were women, and 55% were Caucasian. The mean baseline sodium level was 131 mmol/L and the mean ejection fraction was 32.5%. 222 patients (68.9%) exhibited an increase in sodium during follow-up; in 57 patients (17.7%) the level was unchanged and in 43 patients (13.4%) there was a decrease in sodium level. During a median follow-up of 610 days, there was a strong positive association between change in sodium level and survival (p for trend <0.001); i.e., increased sodium was associated with decreased mortality. In multivariable analysis, change in sodium concentration and higher blood urea nitrogen were the strongest predictors of mortality (both p<0.0001). Conclusions: -Among patients hospitalized with heart failure and hyponatremia, change in serum sodium concentration over time is a strong predictor of long-term survival.

Circ Heart Fail: 15 Jun 2011; epub ahead of print
Madan VD, Novak E, Rich MW
Circ Heart Fail: 15 Jun 2011; epub ahead of print | PMID: 21673193
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Abstract

Forecasting the Impact of Heart Failure in the United States: A Policy Statement From the American Heart Association.

Heidenreich PA, Albert NM, Allen LA, Bluemke DA, ... Council on Clinical Cardiology, Council on Epidemiology and Pr
Background-Heart failure (HF) is an important contributor to both the burden and cost of national healthcare expenditures, with more older Americans hospitalized for HF than for any other medical condition. With the aging of the population, the impact of HF is expected to increase substantially.Methods and results-We estimated future costs of HF by adapting a methodology developed by the American Heart Association to project the epidemiology and future costs of HF from 2012 to 2030 without double counting the costs attributed to comorbid conditions. The model assumes that HF prevalence will remain constant by age, sex, and race/ethnicity and that rising costs and technological innovation will continue at the same rate. By 2030, >8 million people in the United States (1 in every 33) will have HF. Between 2012 and 2030, real (2010$) total direct medical costs of HF are projected to increase from $21 billion to $53 billion. Total costs, including indirect costs for HF, are estimated to increase from $31 billion in 2012 to $70 billion in 2030. If one assumes all costs of cardiac care for HF patients are attributable to HF (no cost attribution to comorbid conditions), the 2030 projected cost estimates of treating patients with HF will be 3-fold higher ($160 billion in direct costs).Conclusions-The estimated prevalence and cost of care for HF will increase markedly because of aging of the population. Strategies to prevent HF and improve the efficiency of care are needed.

Circ Heart Fail: 24 Apr 2013; epub ahead of print
Heidenreich PA, Albert NM, Allen LA, Bluemke DA, ... Council on Clinical Cardiology, Council on Epidemiology and Pr
Circ Heart Fail: 24 Apr 2013; epub ahead of print | PMID: 23616602
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Abstract

Risk-Stratification and Transplant Benefit in Children Listed for Heart Transplant in the United States.

Singh TP, Almond CS, Piercey G, Gauvreau K
Background: -The sickest children among those listed for heart transplant (HT) are also at higher risk of post-transplant mortality. We hypothesized that transplant benefit, defined as percent reduction in risk of 1-yr mortality on receiving HT, increases with higher risk of wait-list mortality. Methods and results: -We analyzed all children < 18 yrs old listed for first HT in the US between 07/2004 and 12/2010. We developed a model for 90-day wait-list mortality (or removal due to deterioration) and stratified listed children into deciles based on their risk of wait-list mortality. Listed children were followed for 1-yr to assess cumulative 1-yr wait-list mortality among the 10 risk-groups. We developed a model for 1-yr post-transplant mortality to estimate the risk of post-transplant mortality for children in each risk-group. Of 2979 listed children, 15% reached the wait-list end-point within 90 days and 18% within 1 yr. Of 2034 HT recipients, 6.8% died within 90 days and 10.8% within 1-yr. The risk of 90-day wait-list mortality increased progressively from 2.4% to 51.6%% from the first to the tenth risk-decile. Transplant benefit increased progressively across the wait-list risk-groups (P<0.001 for trend). However, transplant benefit for children in the top 5% of risk (7.4%) was lower than that for children in the 91(st)-95(th) percentile of risk (10.3%). Conclusions: -Sicker children on the wait-list benefit more from HT unless the post-transplant mortality is predicted to be very high. Whether consideration of transplant benefit in allocation policy can improve overall survival among listed children requires further analysis.

Circ Heart Fail: 23 May 2013; epub ahead of print
Singh TP, Almond CS, Piercey G, Gauvreau K
Circ Heart Fail: 23 May 2013; epub ahead of print | PMID: 23704137
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Abstract

Classification of Acute Decompensated Heart Failure (ADHF): An Automated Algorithm Compared to a Physician Reviewer Panel: The ARIC Study.

Loehr LR, Agarwal SK, Baggett C, Wruck LM, ... Rosamond WD, Heiss G
Background: -An algorithm to classify heart failure (HF) endpoints inclusive of contemporary measures of biomarkers and echocardiography was recently proposed by an international expert panel. Our objective was to assess agreement of HF classification by this contemporaneous algorithm with that by a standardized physician reviewer panel, when applied to data abstracted from community-based hospital records. Methods and results: -During 2005-2007, all hospitalizations were identified from four U.S. communities under surveillance as part of the Atherosclerosis Risk in Communities (ARIC) study. Potential HF hospitalizations were sampled by ICD discharge codes and demographics from men and women aged 55 years and older. The HF classification algorithm was automated and applied to 2,729 (N=13,854 weighted hospitalizations) hospitalizations in which either BNP measures or ejection fraction were documented (mean age 75 years). There were 1,403 (54%, N=7,534 weighted) events classified as acute, decompensated HF (ADHF) by the automated algorithm, and 1,748 (68%, N=9,276 weighted) such events by the ARIC reviewer panel. The chance-corrected agreement between ADHF by physician reviewer panel and the automated algorithm was moderate (Kappa=0.39). Sensitivity and specificity of the automated algorithm with ARIC reviewer panel as the referent standard was 0.68 (95% CI, 0.67 - 0.69), and 0.75 (95% CI, 0.74 - 0.76), respectively. Conclusions: -Although the automated classification improved efficiency and decreased costs, its accuracy in classifying HF hospitalizations was modest compared to a standardized physician reviewer panel.

Circ Heart Fail: 06 May 2013; epub ahead of print
Loehr LR, Agarwal SK, Baggett C, Wruck LM, ... Rosamond WD, Heiss G
Circ Heart Fail: 06 May 2013; epub ahead of print | PMID: 23650310
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Abstract

Impaired Left Ventricular Mechanics in Pulmonary Arterial Hypertension: Identification of a Cohort at High Risk.

Hardegree EL, Sachdev A, Fenstad ER, Villarraga HR, ... Pellikka PA, Kane GC
Background: -Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling and right heart failure. The right (RV) and left ventricles (LV) do not function in isolation, sharing a common pericardial sac and interventricular septum. We sought to define the clinical and prognostic significance of ventricular interdependence in PAH and its association with left ventricular filling patterns through speckle-tracking strain echocardiography. Methods and results: -Echocardiography was performed in 71 adults with a new diagnosis of PAH. To separately analyze LV and RV function, we measured peak systolic longitudinal and circumferential strain of the LV and RV. Survival was assessed over two years. Patients had dilated right-sided chambers (RA volume index 44±19 mL/m(2); RV end-diastolic area 34±9 cm(2)), and reduced RV function (RV fractional area change 28±12%). Speckle tracking echocardiography revealed significant reductions in RV free wall peak systolic strain (-15±3%). Despite normal LV size and normal conventional measures of LV systolic function (end-diastolic dimension 42±6 mm; ejection fraction 65±8%; cardiac index 2.6±0.8 L/min/m(2)), patients had reduced LV free wall systolic strain (-15±3%). Decreased LV free wall systolic strain was associated with a delayed relaxation mitral inflow Doppler pattern, p=0.0002. During 2 years follow-up, 19 patients (27%) died. LV strain was associated with increased mortality (unadjusted HR 2.40 per 5% decrease in LV free wall strain, 1.22-4.68), which remained significant when adjusted for age, sex, WHO functional class, and PAH etiology (HR 3.11, 1.38-7.20). Conclusions: -The pressure loading in PAH results in geometric alterations and functional decline of the RV, with marked reduction in RV systolic strain. Despite preservation of LVEF, LV systolic strain was also reduced and associated with early mortality, highlighting the significance of ventricular interdependence in PAH.

Circ Heart Fail: 26 May 2013; epub ahead of print
Hardegree EL, Sachdev A, Fenstad ER, Villarraga HR, ... Pellikka PA, Kane GC
Circ Heart Fail: 26 May 2013; epub ahead of print | PMID: 23709658
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Abstract

Right Ventricular Response to Intensive Medical Therapy in Advanced Decompensated Heart Failure.

Verhaert D, Mullens W, Borowski AG, Popovic ZB, ... Thomas JD, Tang WH
Background: -Right ventricular (RV) systolic dysfunction is a strong predictor of adverse outcome in heart failure, yet assessing it quantitatively or impact with therapy is difficult. Our objective is to compare clinical significance of changes in RV echocardiographic indices in response to intensive medical treatment in patients admitted with advanced decompensated heart failure (ADHF). Methods and results: -Serial comprehensive echocardiography was performed in 62 consecutive ADHF subjects, and adverse events (death, cardiac transplant, assist device, or heart failure re-hospitalization) were prospectively documented. RV peak systolic strain (RVPSS) was assessed using speckle-tracking longitudinal strain analysis as the average of the basal, mid and apical segment of the RV free wall. Other conventional parameters of RV function (RV fractional area change, myocardial performance index, tricuspid annular peak systolic excursion and tissue Doppler peak tricuspid annular systolic velocity) were measured for comparison. In our study cohort (left ventricular ejection fraction 26+/-10%, cardiac index 2.0+/-0.6 l/min/m(2)), overall mean RVPSS was -14+/-4% at baseline and -15+/-4% at 48-72 hours (p=0.27). Among all the RV functional indices measured, only RVPSS at 48-72 hours was associated with adverse events (p=0.02). In particular, improvement in RVPSS after intensive medical treatment was associated with lower adverse events in this patient population (26% versus 78%, Hazard Ratio 0.13 [95% confidence interval 0.02-0.84], p = 0.02). Conclusions: -Dynamic improvement in RV mechanics in response to intensive medical therapy was associated with lower long-term adverse events in patients with ADHF when compared to those without improvement.

Circ Heart Fail: 23 Feb 2010; epub ahead of print
Verhaert D, Mullens W, Borowski AG, Popovic ZB, ... Thomas JD, Tang WH
Circ Heart Fail: 23 Feb 2010; epub ahead of print | PMID: 20176715
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Abstract

Incidence, Determinants, and Prognostic Significance of Hyperkalemia and Worsening Renal Function in Patients with Heart Failure Receiving the Mineralocorticoid Receptor Antagonist Eplerenone or Placebo Additional to Optimal Medical Therapy: Results from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF).

Rossignol P, Dobre D, McMurray JJ, Swedberg K, ... Pitt B, Zannad F
-Mineralocorticoid receptor antagonists (MRA) improve outcomes in patients with systolic heart failure (HF), but may induce a worsening of renal function (WRF) and/or hyperkalemia (HK). We assessed the risk factors for MRA-related WRF and for HK, as well as the association between HK and WRF with clinical outcomes in the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) Methods and results: -Serial changes in estimated glomerular filtration rate (eGFR) and in serum potassium were available in 2737 patients during a median 21-month follow-up. HK variably defined as serum K>4.5, 5 or 5.5 mmol/L occurred in 74.7 %, 32.5 %, and 8.9 % of EMPHASIS-HF patients, respectively. WRF defined as a decrease in eGFR > 20% or >30% from baseline occurred in 27% and 14% of patients, respectively. Patients assigned eplerenone displayed modest and early but significant and persistent i) rise in serum potassium, and ii) reduction in eGFR compared with placebo. In multivariate analyses, eplerenone was associated with a higher incidence of WRF and HK, which were interrelated and also associated with baseline patient characteristics (e.g. age ≥75 years, hypertension, diabetes, non-white race, ejection fraction <30%, and treatment with an antiarrythmics drug or loop diuretic). Eplerenone retained its survival benefits, without any significant interaction with the association between HK >5.5 mmol/l only and WRF and worse outcomes.

Circ Heart Fail: 02 Dec 2013; epub ahead of print
Rossignol P, Dobre D, McMurray JJ, Swedberg K, ... Pitt B, Zannad F
Circ Heart Fail: 02 Dec 2013; epub ahead of print | PMID: 24297687
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Abstract

Risk Factors for Adverse Outcomes by Left Ventricular Ejection Fraction in a Contemporary Heart Failure Population.

Allen LA, Magid DJ, Gurwitz JH, Smith DH, ... Sung SH, Go AS
Background: -Although heart failure (HF) is a syndrome with important differences in response to therapy by left ventricular ejection fraction (LVEF), existing risk stratification models typically group all HF patients together. The relative importance of common predictor variables for important clinical outcomes across strata of LVEF is relatively unknown. Methods and results: -We identified all members with HF between 2005 and 2008 from 4 integrated health care systems in the Cardiovascular Research Network. LVEF was categorized as preserved (LVEF ≥50% or normal), borderline (41-49% or mildly reduced), and reduced (≤40% or moderately to severely reduced). We used Cox regression models to identify independent predictors of death and hospitalization by LVEF category. Among 30,094 ambulatory adults with HF, mean age was 74 years and 46% were women. LVEF was preserved in 49.5%, borderline in 16.2%, and reduced in 34.3% of patients. Over a median follow up of 1.8 years (IQR 0.8-3.1), 8,060 (26.8%) patients died, 8,108 (26.9%) were hospitalized for HF, and 20,272 (67.4%) were hospitalized for any reason. In multivariable models, nearly all tested covariates performed similarly across LVEF strata for the outcome of death from any cause, as well as for HF-related and all-cause hospitalizations. Conclusions: -We found that in a large, diverse contemporary HF population, risk assessment was strikingly similar across all LVEF categories. These data suggest that, although many HF therapies are uniquely applied to patients with reduced LVEF, individual prognostic factor performance does not appear to be significantly related to level of left ventricular systolic function.

Circ Heart Fail: 26 May 2013; epub ahead of print
Allen LA, Magid DJ, Gurwitz JH, Smith DH, ... Sung SH, Go AS
Circ Heart Fail: 26 May 2013; epub ahead of print | PMID: 23709659
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Abstract

Plasma Vitamin C But Not Vitamin E Is Associated with Reduced Risk of Heart Failure in Older Men.

Wannamethee SG, Bruckdorfer KR, Shaper AG, Papacosta O, Lennon L, Whincup PH
Background: -Oxidative stress has been implicated in the pathogenesis of heart failure (HF). However, data on the association between antioxidant intakes and circulating levels and risk of incident HF in the older general population are limited. We have examined prospectively the associations between plasma vitamin C and E, dietary intakes of vitamin C and E and incident HF. Methods and results: -Prospective study of 3919 men aged 60-79 years with no prevalent HF followed up for a mean period of 11 years, in whom there were 263 incident HF cases. Higher plasma vitamin C level was associated with significantly lower risk of incident HF in both men with and without previous myocardial infarction (MI) after adjustment for lifestyle characteristics, diabetes, blood lipids, blood pressure and heart rate [hazards ratio (HR) (95%CI) 0.81 (0.70,0.93) and 0.75 (0.59,0.97) for a 1SD increase in log vitamin C respectively]. Plasma vitamin E and dietary vitamin C intake showed no association with HF. High levels of dietary vitamin E intake (which correlated weakly with plasma vitamin E) were associated with increased risk of HF in men with no previous MI even after adjustment [adjusted HR (95%CI) 1.23 (1.06,1.42) for a 1SD increase]. Conclusions: -Higher plasma Vitamin C is associated with a reduced risk of HF in older men with and without MI. High intake of dietary vitamin E may be associated with increased HF risk. Primary intervention trials assessing the effect of vitamin C supplements on HF risk in the elderly are needed.

Circ Heart Fail: 03 Jun 2013; epub ahead of print
Wannamethee SG, Bruckdorfer KR, Shaper AG, Papacosta O, Lennon L, Whincup PH
Circ Heart Fail: 03 Jun 2013; epub ahead of print | PMID: 23729199
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Abstract

Treatment of Obstructive Hypertrophic Cardiomyopathy Symptoms and Gradient Resistant to First-Line Therapy with Beta-Blockade or Verapamil.

Sherrid MV, Shetty A, Winson G, Kim B, ... Balaram SK, Swistel DG
Background: -There is controversy about preferred methods to relieve obstruction in hypertrophic cardiomyopathy (HCM) patients still symptomatic after beta-blockade or verapamil. Methods and results: -Of 737 patients prospectively registered at our institution, 299 (41%) required further therapy for obstruction for limiting symptoms, rest gradient 61±45, provoked gradient 115±49 mmHg, followed 4.8 years. Disopyramide was added in 221 (74%) and pharmacologic control of symptoms was achieved in 141 (64%). Overall, 138 (46%) patients had surgical relief of obstruction (91% myectomy), and 6 (2%) alcohol septal ablation. At follow-up resting gradients in the 299 patients had decreased from 61±44 to 10±25 mmHg, p<0.0001; NYHA class decreased from 2.7±0.7 to 1.8±0.5, p<0.0001. Kaplan-Meier survival at 10 years in the 299 advanced-care patients was 88% and did not differ from non-obstructed patients (p=0.28). Only one patient had sudden death, a low annual rate of 0.06%/year. KM survival at 10 years in the advanced-care patients did not differ from that expected in a matched cohort of the US population (p=0.90). Conclusions: -Patients with obstruction and symptoms resistant to initial pharmacologic therapy with beta-blockade or verapamil may realize meaningful symptom relief and low mortality through stepped management, adding disopyramide in appropriately selected patients, and when needed, by surgical myectomy.

Circ Heart Fail: 23 May 2013; epub ahead of print
Sherrid MV, Shetty A, Winson G, Kim B, ... Balaram SK, Swistel DG
Circ Heart Fail: 23 May 2013; epub ahead of print | PMID: 23704138
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Abstract

Central and Peripheral Blood Flow During Exercise with a Continuous-Flow Left Ventricular Assist-Device: Constant vs. Increasing Pump Speed. A Pilot Study.

Brassard P, Jensen AS, Nordsborg N, Gustafsson F, ... Secher NH, Madsen PL
Background: -End-stage heart failure is associated with impaired cardiac output (CO) and organ blood flow. We determined whether CO and peripheral perfusion are maintained during exercise in patients with an axial-flow left ventricular assist device (LVAD) and whether an increase in LVAD pump speed with work rate would increase organ blood flow. Methods and results: -Invasively determined CO and leg blood flow and Doppler-determined cerebral perfusion were measured during two incremental cycle exercise tests on the same day in eight patients provided with a HeartMate II(®) LVAD. In random order, patients exercised both with a constant (~9775 rpm) and with an increasing pump speed (+400 rpm per exercise stage). At 60 Watts, the elevation in CO was more pronounced with increased pump speed (8.7±0.6 vs. 8.1±1.1 L min(-1); mean±SD; P=0.05), but at maximal exercise, increases in CO (from 7.0±0.9 to 13.6±2.5 L min(-1); P<0.01) and leg blood flow (0.7 (0.5-0.8) to 4.4 (3.9-4.8) L min(-1) per leg; median (range); P<0.001) were similar with both pumping modes. Normally middle cerebral artery mean flow velocity increases from ~50 to ~65 cm sec(-1) during exercise, but in LVAD patients with a constant pump speed it was low at rest (39±14 cm sec(-1)) and remained unchanged during exercise, whereas in patients with increasing pump speed, it increased by 5.2±2.8 cm sec(-1) at 60 Watts (P<0.01). Conclusions: -With maximal exercise, the axial-flow LVAD supports near-normal increments in cardiac output and leg perfusion, but cerebral perfusion is poor. Increased pump speed augments cerebral perfusion during exercise.

Circ Heart Fail: 18 Jul 2011; epub ahead of print
Brassard P, Jensen AS, Nordsborg N, Gustafsson F, ... Secher NH, Madsen PL
Circ Heart Fail: 18 Jul 2011; epub ahead of print | PMID: 21765126
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Abstract

Effects of physical activity and sedentary time on the risk of heart failure.

Young DR, Reynolds K, Sidell M, Brar S, ... Caan B, Quinn VP
Background- Although the benefits of physical activity for risk of coronary heart disease are well established, less is known about its effects on heart failure (HF). The risk of prolonged sedentary behavior on HF is unknown. Methods and results- The study cohort included 82 695 men aged ≥45 years from the California Men\'s Health Study without prevalent HF who were followed up for 10 years. Physical activity, sedentary time, and behavioral covariates were obtained from questionnaires, and clinical covariates were determined from electronic medical records. Incident HF was identified through International Classification of Diseases, Ninth Revision codes recorded in electronic records. During a mean follow-up of 7.8 years (646 989 person-years), 3473 men were diagnosed with HF. Controlling for sedentary time, sociodemographics, hypertension, diabetes mellitus, unfavorable lipid levels, body mass index, smoking, and diet, the hazard ratio (95% confidence interval [CI]) of HF in the lowest physical activity category compared with those in the highest category was 1.52 (95% CI, 1.39-1.68). Those in the medium physical activity category were also at increased risk (hazard ratio, 1.17 [95% CI, 1.06-1.29]). Controlling for the same covariates and physical activity, the hazard ratio (95% CI) of HF in the highest sedentary category compared with the lowest was 1.34 (95% CI, 1.21-1.48). Medium sedentary time also conveyed risk (hazard ratio, 1.13 [95% CI, 1.04-1.24]). Results showed similar trends across white and Hispanic subgroups, body mass index categories, baseline hypertension status, and prevalent coronary heart disease. Conclusions- Both physical activity and sedentary time may be appropriate intervention targets for preventing HF.

Circ Heart Fail: 21 Jan 2014; 7:21-7
Young DR, Reynolds K, Sidell M, Brar S, ... Caan B, Quinn VP
Circ Heart Fail: 21 Jan 2014; 7:21-7 | PMID: 24449810
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Abstract

Invasive Measures of Afterload in Low Gradient Severe Aortic Stenosis with Preserved Ejection Fraction.

Eleid MF, Nishimura RA, Borlaug BA, Sorajja P
Background: -The pathophysiology of low flow, low gradient severe aortic stenosis (LGSAS) with preserved ejection fraction (EF) is poorly understood. It has been proposed that abnormalities of the arterial circulation are a major contributor to this syndrome. Methods and results: -We invasively examined systemic arterial afterload (effective arterial elastance, Ea; total arterial compliance, Ca; and systemic vascular resistance index, SVRI) in patients with LGSAS (mean gradient <40mmHg; aortic valve area <1.0 cm(2)) and preserved EF (≥50%), and compared these findings to patients with high gradient (≥40 mmHg) severe aortic stenosis (HGSAS) and moderate AS (mean gradient < 40mmHg; aortic valve area >1.0 cm(2)). Patients with LGSAS (n=36), HGSAS (n=31) and moderate AS (n=19) were similar with respect to age, sex, body size, symptoms, co-morbidities, and EF. Aortic valve area was similar between LGSAS and HGSAS groups, but the LGSAS patients had reduced stroke volume index and cardiac index (p=0.003 for both). In comparison to HGSAS and moderate AS patients, measures of afterload including Ea (4.02 ± 0.98 vs. 3.13 ± 0.81 and 3.06 ± 0.79 mmHg*m(2)/mL; p<0.0001) and SVRI (3116 ± 799 vs. 2515 ± 645 and 2380 ± 546 dyn•s•m(2)/cm(5); p=0.001) were significantly higher in LGSAS, while Ca was lower (0.46 ± 0.16 vs. 0.57 ± 0.13 and 0.59 ± 0.19 mL/m(2)/mmHg; p=0.002). All invasive measures of arterial afterload were related to stroke volume index. Conclusions: -Patients with LGSAS and preserved EF display elevated arterial afterload compared to patients with HGSAS and moderate AS. These findings identify systemic arterial effects that contribute to the hemodynamic presentation in patients with LGSAS, and help to further define this entity.

Circ Heart Fail: 26 May 2013; epub ahead of print
Eleid MF, Nishimura RA, Borlaug BA, Sorajja P
Circ Heart Fail: 26 May 2013; epub ahead of print | PMID: 23709656
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Abstract

Changing Characteristics and Mode of Death Associated with Chronic Heart Failure Due to Left Ventricular Systolic Dysfunction: A Study Across Therapeutic Eras.

Cubbon RM, Gale CP, Kearney LC, Schechter CB, ... Witte KK, Kearney MT
Background: -Therapies for patients with chronic heart failure due to left ventricular systolic dysfunction have advanced substantially over recent decades. The cumulative effect of these therapies on mortality, mode of death, symptoms and clinical characteristics has yet to be defined. Methods and results: -Comparison of two prospective cohort studies of outpatients with chronic heart failure due to left ventricular systolic dysfunction performed between 1993 and 1995 (historical cohort: n=281) and 2006 and 2009 (contemporary cohort: n=357). In the historical cohort 83% were prescribed angiotensin converting enzyme inhibitors and 8.5% beta-adrenoceptor antagonists, compared to 89% and 80% respectively in the contemporary cohort. Mortality over the first year of follow-up declined from 12.5% to 7.8% between eras (P=0.04) and sudden death contributed less to contemporary mortality (33.6% vs. 12.7%; P<0.001). New York Heart Association Class declined between eras (P<0.001). QTc dispersion across the chest leads declined from 85ms (2) to 34ms (1) and left ventricular end diastolic dimensions declined from 65mm (0.6) to 59mm (0.5) (both P<0.001). Conclusions: -Survival has significantly improved in patients with chronic heart failure due to left ventricular systolic dysfunction over the past 15 years; furthermore, sudden death makes a much smaller contribution to mortality, and non-cardiac mortality a correspondingly greater contribution. This has been accompanied by an improvement in symptoms and some markers of adverse electrical and structural left ventricular remodelling.

Circ Heart Fail: 12 May 2011; epub ahead of print
Cubbon RM, Gale CP, Kearney LC, Schechter CB, ... Witte KK, Kearney MT
Circ Heart Fail: 12 May 2011; epub ahead of print | PMID: 21562056
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Abstract

Socioeconomic Status, Medicaid Coverage, Clinical Comorbidity and Rehospitalization or Death following an Incident Heart Failure Hospitalization: ARIC Cohort (1987-2004).

Foraker RE, Rose KM, Suchindran CM, Chang PP, McNeill AM, Rosamond WD
Background: -Among heart failure (HF) patients, early readmission or death and repeat hospitalizations may be indicators of poor disease management or more severe disease. Methods and results: -We assessed the association of neighborhood median household income (nINC) and Medicaid status with rehospitalization or death in the Atherosclerosis Risk in Communities cohort study (1987-2004) following an incident HF hospitalization in the context of individual socioeconomic status, and evaluated the relationship for modification by demographic and comorbid factors. We used generalized linear Poisson mixed models to estimate rehospitalization rate ratios and 95% confidence intervals (RR, 95% CI) and Cox regression to estimate hazard ratios (HR, 95% CI) of rehospitalization or death. In models controlling for race/study community, gender, age at HF diagnosis, body mass index, hypertension, educational attainment, alcohol use and smoking, persons with a high burden of comorbidity who were living in low nINC areas at baseline had an elevated hazard of all-cause rehospitalization (1.40, 1.10-1.77), death (1.36, 1.02-1.80), and rehospitalization or death (1.36, 1.08-1.70)-as well as increased rates of hospitalizations-compared to those with a high burden of comorbidity living in high nINC areas. Medicaid recipients with a low level of comorbidity had an increased hazard of all-cause rehospitalization (1.19, 1.05 -1.36) and rehospitalization or death (1.21, 1.07-1.37), and a higher rate of repeat hospitalizations compared to non-Medicaid recipients. Conclusions: -Comorbidity burden appears to influence the association between nINC, Medicaid status and rehospitalization and death among HF patients.

Circ Heart Fail: 24 Mar 2011; epub ahead of print
Foraker RE, Rose KM, Suchindran CM, Chang PP, McNeill AM, Rosamond WD
Circ Heart Fail: 24 Mar 2011; epub ahead of print | PMID: 21430286
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Abstract

New Predictive Models of Heart Failure Mortality Using Time-Series Measurements and Ensemble Models.

Subramanian D, Subramanian V, Deswal A, Mann D
Background: -Morbidity and mortality associated with heart failure remains high. A wide variety of demographic and clinical factors, as well as biomarkers are associated with increased mortality. Despite this, most multivariate predictive models for heart failure mortality have predictive accuracies characterized by a C-statistic (area under the receiver operating curve) of around 0.74. Methods and results: -We analyzed data on 963 patients enrolled in the Vesnarinone Evaluation of Survival Trial (VEST), including circulating levels of two cytokines (TNF and IL-6) and their receptors sampled at baseline, and at 8, 16 and 24 weeks. We built multivariate logistic regression models using standard clinical variables and time-series of cytokine and cytokine receptor levels, using independent components analysis to handle collinearity among cytokine measurements, and L2-penalized stepwise regression for variable selection. We also built ensemble models with these data using gentle boosting. Our multivariate logistic regression model using time-series cytokine measurements predicts one-year mortality significantly better (p=0.001) than the baseline model, with a C-statistic of 0.81±0.03. Without the cytokines, the baseline model has a C-statistic of 0.73±0.03, and with only baseline cytokine and cytokine receptor levels added, the model has a C-statistic of 0.74±0.04. An ensemble model of 100 decision stumps with serial cytokine measurements has a significantly better (p=0.04) C-statistic of 0.84±0.02.An ensemble model with baseline cytokine data and without the serial measurements has a C-statistic of 0.74±0.04. Conclusions: -Significant gains in accuracy of one year mortality prediction in chronic heart failure can be obtained by using logistic regression models that incorporate serial measurements of biomarkers such as cytokine and cytokine receptor levels. Ensemble models capture inherent variability in large patient populations, and boost predictive accuracy through the use of time-series measurements.

Circ Heart Fail: 12 May 2011; epub ahead of print
Subramanian D, Subramanian V, Deswal A, Mann D
Circ Heart Fail: 12 May 2011; epub ahead of print | PMID: 21562057
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Abstract

Coronary Collaterals Predict Improved Survival and Allograft Function in Patients with Coronary Allograft Vasculopathy.

Lavine KJ, Sintek M, Novak E, Ewald G, ... Pfeifer J, Mann D
Background: -Despite improvements in the care of patients who have received cardiac transplants, coronary allograft vasculopathy (CAV) remains the most prevalent cause of late allograft failure and cardiac mortality. Few proven therapies are available for this important disease. The presence of coronary collaterals imparts a favorable prognosis in patients with native ischemic heart disease; however, the impact of collaterals in CAV is unknown. Methods and results: -To determine whether the development of coronary collaterals is associated with improved outcomes in patients with CAV, we performed a retrospective analysis of patients followed in the heart transplant program at Barnes Jewish Hospital from 1994-2008. The primary endpoints included all cause mortality and the composite of all cause mortality, retransplantation, and inotrope dependence. We screened 485 patients and identified 59 (12%) subjects with moderate to severe CAV. Angiographically visible coronary collaterals were present in 34 (57%) subjects. Kaplan-Meier and Cox multivariable analyses revealed that patients with collaterals had reduced incidence of all cause mortality HR 0.20, p<0.001 and the composite endpoint HR 0.17, p<0.001. In addition, patients with collaterals had less severe heart failure symptoms as measured by NYHA class. Immunostaining of biopsy specimens revealed that among patients with CAV, the presence of coronary collaterals correlated with increased microvascular density, reduced fibrosis and lower LVEDP. Conclusions: -Together, these data demonstrate that the presence of coronary collaterals predicts a favorable prognosis in patients with CAV and suggests that interventions aimed at promoting collateral and microvascular growth may serve as effective therapies for this disease.

Circ Heart Fail: 26 May 2013; epub ahead of print
Lavine KJ, Sintek M, Novak E, Ewald G, ... Pfeifer J, Mann D
Circ Heart Fail: 26 May 2013; epub ahead of print | PMID: 23709657
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Abstract

Post-Transcriptional Regulation of Alpha-1-Antichymotrypsin by miR-137 in Chronic Heart Failure and Mechanical Support.

Lok SI, van Mil A, Bovenschen N, van der Weide P, ... de Jonge N, de Weger RA
Background: -Better understanding of the molecular mechanisms of remodeling has become a major objective of heart failure (HF) research to stop or reverse its progression. Left ventricular assist devices (LVADs) are being used in patients with HF, leading to partial reverse remodeling. In the present study, proteomics identified significant changes in alpha-1-antichymotrypsin (ACT) levels during LVAD support. Moreover, the potential role of ACT in reverse remodeling was studied in detail. Methods and results: -Expression of ACT mRNA (Q-PCR) decreased significantly in post-LVAD myocardial tissue compared to pre-LVAD tissue (n=15; p<0.01). Immunohistochemistry revealed that ACT expression and localization changed during LVAD support. Circulating ACT levels were elevated in HF patients (n=18) as compared to healthy controls (n=6; p=0.001) and normalized upon 6 months of LVAD support. Since increasing evidence implicates that microRNAs (miRs) are involved in myocardial disease processes, we also investigated whether ACT is post-transcriptional regulated by miRs. Bioinformatics analysis pointed miR-137 as a potential regulator of ACT. The miR-137 expression inversely correlated with ACT mRNA in myocardial tissue. Luciferase activity assays confirmed ACT as a direct target for miR-137 and in situ hybridization indicated that ACT and miR-137 were mainly localized in cardiomyocytes and stromal cells. Conclusions: -High ACT plasma levels in HF normalized during LVAD support, which coincides with decreased ACT mRNA in heart tissue, whereas miR-137 levels increased. MiR-137 directly targeted ACT, thereby indicating that ACT and miR-137 play a role in the pathophysiology of HF and reverse remodeling during mechanical support.

Circ Heart Fail: 02 May 2013; epub ahead of print
Lok SI, van Mil A, Bovenschen N, van der Weide P, ... de Jonge N, de Weger RA
Circ Heart Fail: 02 May 2013; epub ahead of print | PMID: 23640964
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Abstract

Mechanistic Features Associated with Improvement in Mitral Regurgitation Following Cardiac Resynchronization Therapy and Their Relation to Long Term Patient Outcome.

Onishi T, Onishi T, Marek JJ, Ahmed M, ... Saba S, Gorcsan J
Background: -Mechanisms of mitral regurgitation (MR) reduction with cardiac resynchronization therapy (CRT) are complex and their association with long-term outcome unclear. We sought to elucidate mechanistic features of reduction in MR with CRT which impact long-term patient survival. Methods and results: -A prospective longitudinal study of 277 heart failure patients with QRS width ≥120ms, and ejection fraction ≤ 35% for CRT was performed. Quantitative echocardiography including dyssynchrony analysis was performed at baseline. MR was quantified by color Doppler before and 6 months after CRT. Pre-defined endpoints of death, transplant or left ventricular (LV) assist device (LVAD) were tracked over 4 years. There were 114 (48%) CRT patients with significant MR (≥ moderate) at baseline; of whom 48 (42%) had MR improvement and 24 (19%) had MR worsening after CRT. The 66 events (47 deaths, 10 transplantations, and 9 LVADs) were strongly associated with significant MR after CRT (hazard ratio 3.58, 95% confidence interval 2.18 to 5.87, p<0.0001). Three echocardiographic features were independently associated with amelioration of significant MR after CRT by multivariable analysis: anteroseptal to posterior wall radial strain dyssynchrony ≥ 200ms, lack of severe LV dilatation (end-systolic dimension index < 29 mm/m(2)), and lack of echocardiographic scar at papillary muscle insertion sites (all p<0.05), and when combined were additively associated with long-term survival (p=0.0001). Conclusions: -Significant MR after CRT was strongly associated with less favorable long term survival. Echocardiographic mechanistic features were identified that were associated with improvement in MR after CRT and favorable long term survival.

Circ Heart Fail: 03 Jun 2013; epub ahead of print
Onishi T, Onishi T, Marek JJ, Ahmed M, ... Saba S, Gorcsan J
Circ Heart Fail: 03 Jun 2013; epub ahead of print | PMID: 23733917
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Abstract

Insulin Resistance and Risk of Incident Heart Failure: Cardiovascular Health Study.

Banerjee D, Biggs ML, Mercer L, Mukamal K, ... Siscovick D, Carnethon M
Background: -Patients with heart failure (HF) have higher fasting insulin levels and a higher prevalence of insulin resistance (IR) as compared with matched controls. IR leads to structural abnormalities in the heart, such as increased left atrial (LA) size, left ventricular (LV) mass, and alterations in transmitral velocity that can precede the diagnosis of HF. It is not known whether IR precedes the development of HF or whether the relationship between IR and HF is present among adults with HF due to non-ischemic heart disease. Methods and results: -We examined 4425 participants (60% female) from the Cardiovascular Health Study after excluding those with HF, myocardial infarction, or treated diabetes at baseline. We used Cox proportional hazards models to estimate the relative risk of incident HF associated with fasting insulin measured at study entry. There were 1216 cases of incident HF (1103 without antecedent MI) during a median follow-up of 12 years (maximum, 19 years). Fasting insulin levels were positively associated with the risk of incident HF (HR = 1.10, 95% CI 1.05, 1.15, per SD change) when adjusted for age, gender, race, field center, physical activity, smoking, alcohol intake, HDL cholesterol, total cholesterol, and systolic blood pressure, and waist circumference. The association between fasting insulin levels and incident HF was similar for HF without antecedent MI (HR= 1.10, 95% CI 1.05, 1.15). Measures of LA size, LV mass, and peak A velocity at baseline were associated both with fasting insulin levels and with heart failure ; however, additional statistical adjustment for these parameters did not completely attenuate the insulin-HF estimate (HR= 1.08, 95% CI 1.03, 1.14 per1-SD increase in fasting insulin). Conclusions: -Fasting insulin was positively associated with adverse echocardiographic features and risk of subsequent HF in CHS participants, including those without an antecedent MI.

Circ Heart Fail: 10 Apr 2013; epub ahead of print
Banerjee D, Biggs ML, Mercer L, Mukamal K, ... Siscovick D, Carnethon M
Circ Heart Fail: 10 Apr 2013; epub ahead of print | PMID: 23575256
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Abstract

The Unrecognized Burden of Osteoporosis-Related Vertebral Fractures in Patients with Heart Failure.

Lyons K, Majumdar SR, Ezekowitz JA
Background: -Heart failure (HF) is associated with several factors that contribute to both reduced bone mineral density and increased risk of osteoporosis-related fractures. Our objectives were to describe the prevalence and predictors of the most common osteoporotic fracture, vertebral compression fractures [VCF], in patients with HF. Methods and results: -We conducted a cross-sectional study in a random sample of patients attending a tertiary care HF Clinic in Edmonton, Alberta, Canada. We collected sociodemographic, clinical, medication, and chest-radiograph information. Primary outcome was board-certified radiologist documented VCF on chest radiographs. Multivariable logistic regression was used to determine independent correlates of VCF. Overall, 623 patients with HF were included; 32% were over 75 years of age, 31% were women, 65% had ischemic cardiomyopathy, and 38% had atrial fibrillation. Prevalence of VCF was 77 of 623 (12%; 95%CI 10 to 15%) and 42 of 77 (55%) patients had multiple fractures. Only 15% of those with VCF were treated for osteoporosis. In multivariable analyses adjusted for age, female sex, weight, and medications, the only remaining predictors independently associated with fracture were atrial fibrillation (present in 42 of 77 [55%] of those with VCF vs. 197 of 540 [36%] of those without; adjusted odds ratio 2.1, 95%CI 1.2 to 3.6, p=0.009) and lipid lowering drugs (used by 36 of 77 [47%] of those with VCF vs. 342 of 540 [63%] of those without; adjusted odds ratio 0.2, 95%CI 0.1-0.9, p=0.03). Conclusions: -About one-tenth of HF patients had a chest-radiograph documented VCF and half of those with VCF had multiple fractures; most (85%) were not on an osteoporosis-specific therapy. A previously unrecognized risk factor-atrial fibrillation-was found to be independently associated with VCF. Chest radiograph reports may represent an important case-finding tool for osteoporosis-specific VCF, particularly in HF patients with atrial fibrillation.

Circ Heart Fail: 11 May 2011; epub ahead of print
Lyons K, Majumdar SR, Ezekowitz JA
Circ Heart Fail: 11 May 2011; epub ahead of print | PMID: 21558449
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Abstract

Do Countries or Hospitals With Longer Hospital Stays for Acute Heart Failure Have Lower Readmission Rates? Findings From ASCEND-HF.

Eapen ZJ, Reed SD, Li Y, Kociol RD, ... Califf RM, Hernandez AF
Background: -Hospital readmission is an important clinical outcome of patients with heart failure. Its relation to length of stay for the initial hospitalization is not clear. Methods and results: -We used hierarchical modeling of data from a clinical trial to examine variations in length of stay across countries and across hospitals in the United States and its association with readmission within 30 days of randomization. Main outcomes included associations between country-level length of stay and readmission rates, after adjustment for patient-level case mix; and associations between length of stay and readmission rates across sites in the United States. Across 27 countries with 389 sites and 6848 patients, mean length of stay ranged from 4.9 to 14.6 days (6.1 days in the United States). Rates of all-cause readmission ranged from 2.5% to 25.0% (17.8% in the United States). There was an inverse correlation between country-level mean length of stay and readmission (r = -0.52; P < .01). After multivariable adjustment, each additional inpatient day across countries was associated with significantly lower risk of all-cause readmission (odds ratio [OR], 0.86; 95% CI, 0.75-0.98; P = .02) and heart failure readmission (OR, 0.79; 95% CI, 0.69-0.99; P = .03). Similar trends were observed across US study sites with regard to readmission for any cause (OR, 0.92; 95% CI, 0.85-1.00; P = .06) and readmission for heart failure (OR, 0.90; 95% CI, 0.80-1.01; P = .07). Across countries and across US sites, longer median length of stay was independently associated with lower risk of readmission. Conclusions: -Countries with longer length of stay for heart failure hospitalizations had significantly lower rates of readmission within 30 days of randomization. These findings may have implications for developing strategies to prevent readmission, defining quality measures, and designing clinical trials in acute heart failure. Clinical trial registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00475852.

Circ Heart Fail: 16 Jun 2013; epub ahead of print
Eapen ZJ, Reed SD, Li Y, Kociol RD, ... Califf RM, Hernandez AF
Circ Heart Fail: 16 Jun 2013; epub ahead of print | PMID: 23770519
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Abstract

Intramyocardial BNP Gene Delivery Improves Cardiac Function Through Distinct Context-Dependent Mechanisms.

Moilanen AM, Rysä J, Mustonen E, Serpi R, ... Vuolteenaho O, Ruskoaho H
Background: -B-type natriuretic peptide (BNP) is an endogenous peptide produced under physiological and pathological conditions mainly by ventricular myocytes. It possesses natriuretic, diuretic, blood pressure lowering and antifibrotic actions that could mediate cardiorenal protection in cardiovascular diseases. In the present study, we used BNP gene transfer to examine functional and structural effects of BNP on left ventricular (LV) remodeling. Methods and results: -Human BNP was overexpressed by using adenovirus mediated gene delivery in normal rat hearts and in hearts during the remodeling process post-infarction and in an experimental model of angiotensin II-mediated hypertension. In healthy hearts, BNP gene delivery into the anterior wall of the LV decreased myocardial fibrosis (P<0.01, n=7-8) and increased capillary density (P<0.05, n=7-8) associated with a 7.3-fold increase in LV BNP peptide levels. Overexpression of BNP improved LV fractional shortening (FS) by 22% (P<0.05, n=6-7) and ejection fraction (EF) by 19% (P<0.05, n=6-7) post-infarction. The favourable effect of BNP gene delivery on cardiac function post-infarction was associated with normalization of cardiac sarcoplasmic reticulum Ca(2+)-ATPase expression and phospholamban Thr17-phosphorylation. BNP gene delivery also improved FS and EF in angiotensin II-mediated hypertension, as well as decreased myocardial fibrosis and LV collagen III mRNA levels, but had no effect on angiogenesis or Ca(2+)-ATPase expression and phospholamban phosphorylation. Conclusions: -Local intramyocardial BNP gene delivery improves cardiac function and attenuates adverse post-infarction and angiotensin II-induced remodeling. These results also indicate that myocardial BNP has pleiotropic, context-dependent favourable actions on cardiac function, and suggest that BNP acts locally as a key mechanical load-activated regulator of angiogenesis and fibrosis.

Circ Heart Fail: 11 May 2011; epub ahead of print
Moilanen AM, Rysä J, Mustonen E, Serpi R, ... Vuolteenaho O, Ruskoaho H
Circ Heart Fail: 11 May 2011; epub ahead of print | PMID: 21558448
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Abstract

Preoperative INTERMACS Profiles Determine Postoperative Outcomes in Critically Ill Patients Undergoing Emergency Heart Transplantation: Analysis of the Spanish National Heart Transplant Registry.

Barge-Caballero E, Segovia-Cubero J, Almenar-Bonet L, Gonzalez-Vilchez F, ... Muñiz-Garcia J, Crespo-Leiro M
Background: -Postoperative outcomes of advanced heart failure patients undergoing ventricular assist device implantation are strongly influenced by their preoperative INTERMACS profiles. We sought to investigate whether a similar association exists in patients undergoing emergency heart transplantation. Methods and results: -By means of the Spanish National Heart Transplant Registry database, we identified 704 adult patients treated with emergency heart transplantation in fifteen Spanish centers between 2000 and 2009. Post-transplant outcomes were analyzed with regard to patient preoperative INTERMACS profiles, which were retrospectively assigned by two blinded cardiologists. Before transplantation, INTERMACS profile 1 ("critical cardiogenic shock") was present in 207 patients, INTERMACS profile 2 ("progressive decline") in 291, INTERMACS profile 3 ("inotropic dependence") in 176 and INTERMACS profile 4 ("resting symptoms") in 30. In-hospital postoperative mortality rates were respectively 43%, 26.8% and 18% in patients with profiles 1, 2 and 3-4 (p<0.001). INTERMACS 1 patients also presented the highest incidence of primary graft failure (1: 31.3%, 2: 22.3%, 3-4: 21.8%, p=0.03) and postoperative need for dialysis (1: 33.2%, 2: 18.9%, 3-4: 21.5%, p <0.001). Adjusted odds-ratios for in-hospital postoperative mortality were 4.38 (CI95% 2.51-7.66) for profile 1 versus 3-4, 2.49 (CI 95% 1.56-3.97) for profile 1 versus 2 and 1.76 (CI95% 1.02-3.03) for profile 2 versus 3-4. Long-term survival after hospital discharge was not influenced by preoperative INTERMACS profiles. Conclusions: -Preoperative INTERMACS profiles determine outcomes after emergency heart transplantation. Results call for a change in policies related to the management of heart transplant candidates presenting with INTERMACS profiles 1 and 2.

Circ Heart Fail: 14 May 2013; epub ahead of print
Barge-Caballero E, Segovia-Cubero J, Almenar-Bonet L, Gonzalez-Vilchez F, ... Muñiz-Garcia J, Crespo-Leiro M
Circ Heart Fail: 14 May 2013; epub ahead of print | PMID: 23674362
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Abstract

A Novel Immunomodulator, FTY-720 Reverses Existing Cardiac Hypertrophy and Fibrosis from Pressure Overload by Targeting NFAT Signaling and Periostin.

Liu W, Zi M, Tsui H, Chowdhury SK, ... Lei M, Wang X
Background: -Hypertension or aortic stenosis causes pressure overload, which evokes hypertrophic myocardial growth. Sustained cardiac hypertrophy eventually progresses to heart failure. Growing evidence indicates that restraining hypertrophy could be beneficial; here we discovered that FTY-720, an immuno-modulator for treating multiple sclerosis, can reverse existing cardiac hypertrophy/fibrosis. Methods and results: -Male C57/Bl6 mice underwent transverse aortic constriction (TAC) for 1 week followed by FTY-720 treatment for 2 weeks under continuing TAC. Compared to vehicle-treated TAC hearts, FTY-720 significantly reduced ventricular mass, ameliorated fibrosis and improved cardiac performance. Mechanistic studies led us to discover that FTY-720 appreciably inhibited NFAT activity. Moreover, we found that in primary cardiomyocytes (rat and human) pertussis toxin (PTX, Gi-coupled receptor inhibitor) substantially blocked the anti-hypertrophic effect of FTY-720. This observation was confirmed in a mouse model of pressure overload. Interestingly, gene array analysis of TAC-hearts revealed that FTY-720 profoundly decreased gene expression of a group of matricellular proteins, of which periostin was prominent. Analysis of periostin protein expression in TAC-myocardium, as well as in rat and human cardiac fibroblasts confirmed the array data. Moreover, we found that FTY-720 treatment or knockdown of periostin protein was able to inhibit TGF-β responsiveness and decrease collagen expression. Conclusions: -FTY-720 alleviates existing cardiac hypertrophy/fibrosis through mechanisms involving negative regulation of NFAT activity in cardiomyocytes and reduction of periostin expression allowing for a more homeostatic extracellular compartment milieu. Together, FTY-720 or its analogues could be a promising new approach for treating hypertrophic/fibrotic heart disease.

Circ Heart Fail: 10 Jun 2013; epub ahead of print
Liu W, Zi M, Tsui H, Chowdhury SK, ... Lei M, Wang X
Circ Heart Fail: 10 Jun 2013; epub ahead of print | PMID: 23753531
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Abstract

Prognostic Value of Exercise Testing During Heart Transplant Evaluation in Children.

Lytrivi ID, Blume ED, Rhodes J, Dillis S, Gauvreau K, Singh TP
Background: -Maximum oxygen consumption (Peak VO2) <50% predicted on exercise testing is a class I indication for heart transplant (HT) listing in children. This recommendation is based on exercise data in adults. We assessed the association of peak VO2<50% predicted during HT evaluation with freedom from death or deterioration in children. Methods and results: -We analyzed all children who underwent exercise testing during HT evaluation at our center between 2002 and 2011. Patients with peak VO2<50% predicted were compared with those with peak VO2≥50% predicted for the composite outcome of (1) death before HT, (2) initiation of mechanical circulatory support, and (3) HT at highest urgency status, using time-to-event analyses. There were 50 children in the study (median age 15 yrs, inter-quartile range 13-17 yrs, 24 female, 18 with palliated single ventricle). Overall, 24 children reached the composite endpoint. Peak VO2<50% predicted was associated with outcome in children with biventricular circulation (Hazard ratio [HR] 4.7, 95% confidence interval [CI] 1.8, 12.3, P<0.001) but not in those with a palliated single ventricle (HR 1.3, CI 0.1, 12.0, P=0.80). Similarly, VE/VCO2 slope ≥34 was associated with outcome in children with biventricular circulation (HR 2.7, 95% CI 1.1, 7.1, P<0.001) but not in children with a palliated single ventricle. Conclusions: -Exercise testing during HT evaluation in children with biventricular circulation identified those at higher risk of death or deterioration in this small study. Larger studies are needed to assess the role of exercise testing during HT evaluation in children with a palliated single-ventricle.

Circ Heart Fail: 11 Apr 2013; epub ahead of print
Lytrivi ID, Blume ED, Rhodes J, Dillis S, Gauvreau K, Singh TP
Circ Heart Fail: 11 Apr 2013; epub ahead of print | PMID: 23580746
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Abstract

The Failing Heart of Patients with Type 2 Diabetes Can Adapt to Extreme Short-Term Increases in Circulating Lipids and Does Not Display Features of Acute Myocardial Lipotoxicity.

Nielsen R, Nørrelund H, Kampmann U, Kim WY, ... Bøtker HE, Wiggers H
Background: -Circulating lipid levels and myocardial lipid content (MyLC) is increased in type 2 diabetes (T2D). This may cause a state of lipotoxicity that compromises left ventricular function and aggravate heart failure. We investigated the relationship between circulating lipid levels, MyLC, and cardiac function together with the acute cardiac effects of high as opposed to low circulating free fatty acid (FFA) and triglyceride (TG) levels in patients with T2D and heart failure. Methods and results: -Eighteen patients underwent 8-hour intralipid/heparin-infusion (high-FFA) and hyperinsulinemic-euglycemic clamping (low-FFA) in a randomized cross-over-designed study. We applied MR-proton-spectroscopy to measure MyLC. Cardiac function was assessed by advanced echocardiography, cardiopulmonary exercise, and MR imaging. MyLC correlated positively with circulating TG (r=0.47, r(2)=0.22, p=0.003) and FFA (r=0.45, r(2)=0.20, p=0.001) levels and inversely with left ventricular ejection fraction (LVEF) (r=-0.54, r(2)=0.29, p=0.004). Circulating FFA concentrations differed between study arms (0.05±0.04mmol/L (low-FFA) vs 1.04±0.27mmol/L (high-FFA), p<0.001) and MyLC increased from 0.78±0.59% (low-FFA) to 1.16±0.73% (high-FFA) (p<0.01). Resting LVEF and global strain did not differ between high- and low-FFA, whereas resting systolic mitral plane velocity (S\'max) was highest during high-FFA (3.6±0.8cm/s (low-FFA) vs. 3.8±0.7cm/s (high-FFA), p=0.02). Peak exercise capacity and oxygen consumption did not differ between the study arms, and neither did post exercise measurements of LVEF, global strain, and S\'max. Conclusions: -Our findings indicate that the failing heart of patients with T2D can adapt to short-term extreme changes in circulating substrates and does not display features of acute myocardial lipotoxicity. Clinical trial registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01192373.

Circ Heart Fail: 03 Jun 2013; epub ahead of print
Nielsen R, Nørrelund H, Kampmann U, Kim WY, ... Bøtker HE, Wiggers H
Circ Heart Fail: 03 Jun 2013; epub ahead of print | PMID: 23733915
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Abstract

An Evaluation of the Role of Endomyocardial Biopsy in 851 Patients With Unexplained Heart Failure From 2000-2009.

Bennett MK, Gilotra NA, Harrington C, Rao S, ... Halushka MK, Russell SD
Background: -Endomyocardial biopsy (EMB) is often considered when the etiology of heart failure cannot be determined by non-invasive testing. Uncertainty remains about the diagnostic and clinical utility of EMB in various clinical scenarios. Methods and results: -We examined the characteristics of a cohort of patients with unexplained heart failure who underwent EMB at a tertiary care medical center. We categorized each patient into a clinical scenario as outlined by the 2007 AHA/ACC/ESC guidelines and determined the number of times EMB provided a diagnosis or altered the clinical course. A total of 851 patients underwent EMB from 2000-2009. Overall, 25.5% of EMB provided a diagnosis and 22.7% changed clinical course. Heart failure associated with unexplained restrictive cardiomyopathy was the most common clinical scenario, comprising 33.6% (286/851) of EMB, and eighty-four (29.4%) of these EMB were diagnostic. EMB for unexplained heart failure of less than two weeks duration had a diagnostic yield at 35% (39/109). There were four uncommon scenarios where EMB had a high diagnostic and clinical yield. There were 16 complications for an overall rate of 1.9%. Conclusions: -We confirm that EMB is useful in acute onset unexplained cardiomyopathy. We demonstrate a role for EMB in suspected infiltrative disease and in the management of rare clinical scenarios such as suspected hypersensitivity myocarditis, anthracycline cardiomyopathy, cardiac tumors, and ARVD/C. Our results suggest low utility of EMB in chronic heart failure that responds to usual care.

Circ Heart Fail: 03 Jun 2013; epub ahead of print
Bennett MK, Gilotra NA, Harrington C, Rao S, ... Halushka MK, Russell SD
Circ Heart Fail: 03 Jun 2013; epub ahead of print | PMID: 23733916
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Abstract

Plasma Biomarkers That Reflect Determinants of Matrix Composition Identify the Presence of Left Ventricular Hypertrophy and Diastolic Heart Failure.

Zile MR, Desantis SM, Baicu CF, Stroud RE, ... Mehurg SM, Spinale FG
Background: -Chronic pressure overload (such as arterial hypertension) may cause left ventricular (LV) remodeling, alterations in cardiac function, and the development of diastolic heart failure. Changes in the composition of the myocardial extracellular matrix (ECM) may contribute to the development of pressure-overload (PO) induced LV remodeling. We hypothesized that a specific pattern of plasma biomarker expression that reflected changes in these pathophysiologic mechanisms would have diagnostic application to identify: 1- patients who have developed LV hypertrophy and 2- patients with LV hypertrophy who have developed diastolic heart failure. Methods and results: -Plasma concentration of 17 biomarkers (MMP-1, 2, 3, 7, 8, 9, TIMP-1, 2, 3, 4, NT-proBNP, cardiotrophin, osteopontin, sRAGE, CITP, PINP, PIIINP), an echocardiogram, and 6-minute hall walk were performed on 241 referent control subjects, 144 patients with LV hypertrophy (LVH) but no evidence of heart failure, and 61 patients with LV hypertrophy and diastolic heart failure (DHF). A plasma multi-biomarker panel consisting of increased MMP-7, MMP-9, TIMP-1, PIIINP, and NT-proBNP predicted the presence of LVH with an AUC of 0.80. A plasma multi-biomarker panel consisting of increased MMP-2, TIMP-4, PIIINP and decreased MMP-8 predicted the presence of DHF with an AUC of 0.79. These multi-biomarkers panels performed better than any single biomarker including NT-proBNP, and better than using clinical co-variates alone (AUC = 0.73 for LVH, 0.68 for DHF). Conclusions: -Plasma biomarkers reflecting changes in ECM fibrillar collagen homeostasis, combined into a multi-biomarker panel, have discriminative value in identifying the presence of structural remodeling (LVH) and clinical disease (DHF).

Circ Heart Fail: 25 Feb 2011; epub ahead of print
Zile MR, Desantis SM, Baicu CF, Stroud RE, ... Mehurg SM, Spinale FG
Circ Heart Fail: 25 Feb 2011; epub ahead of print | PMID: 21350055
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Abstract

Ultrafiltration in Heart Failure with Preserved Ejection Fraction: Comparison with Systolic Heart Failure Patients.

Jefferies JL, Bartone C, Menon S, Egnaczyk GF, O\'Brien TM, Chung ES
Background: -Ultrafiltration (UF) is a widely used technology for inpatient management of acute decompensated heart failure (ADHF) in patients with volume overload. However, the safety and efficacy of UF in patients with heart failure and preserved left ventricular ejection fraction (LVEF, HFPEF) need further clarification. We hypothesized that UF could be used in this population with outcomes similar to ADHF patients with low LVEF (HFLEF). Methods and results: -Prospective evaluation was performed on two patient cohorts admitted to a single institution for ADHF and treated with UF: HFLEF (LVEF ≤ 40%, n=87) and HFPEF (LVEF > 40%, n=97). Selected demographic and clinical data were compared including clinical and serologic information as well as in-hospital and 90 day post discharge mortality. HFPEF patients were more likely to be female, have higher blood pressures, and less likely to have ischemic heart disease. There were no significant differences in total weight loss (7.7% in HFLEF and 7.0% in HFPEF), electrolyte and renal disturbances, or in-hospital mortality (3.4% in HFLEF and 3.3% in HFPEF) between the two groups. Mortality at 90 days tended to be greater in HELEF (24.1%) than in HFPEF (15.5%). Conclusions: -Therapeutic responses in patients with HFPEF meeting current indication for UF are similar to those with HFLEF Larger studies are warranted to better characterize acute HF management with UF in this population.

Circ Heart Fail: 04 Jun 2013; epub ahead of print
Jefferies JL, Bartone C, Menon S, Egnaczyk GF, O'Brien TM, Chung ES
Circ Heart Fail: 04 Jun 2013; epub ahead of print | PMID: 23735537
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Abstract

Impaired Assembly and Post-Translational Regulation of 26S Proteasome in Human End Stage Heart Failure.

Day SM, Divald A, Wang P, Davis F, ... Jones R, Powell SR
Background: -This study examined the hypothesis that 26S proteasome dysfunction in human end stage heart failure is associated with decreased docking of the 19S regulatory particle to the 20S proteasome. Previous studies have demonstrated that 26S proteasome activity is diminished in human end stage heart failure associated with oxidation of the 19S regulatory particle Rpt5 subunit. Docking of the 19S regulatory particle to the 20S proteasome requires functional Rpt subunit ATPase activity and phosphorylation of the α-type subunits. Methods and results: -An enriched proteasome fraction was prepared from 7 human non-failing and 10 failing heart explants. Native gel electrophoresis assessed docking of 19S- to 20S proteasome revealing three proteasome populations (20S-, 26S-, and 30S proteasomes). In failing hearts, 30S proteasomes were significantly lower (P=0.048) by 37% suggesting diminished docking. Mass spectrometry-based phosphopeptide analysis demonstrated that the relative ratio of phosphorylated:non-phosphorylated α7 subunit (serine250) of the 20S proteasome was significantly less (P=0.011) by almost 80% in failing hearts. Rpt ATPase activity was determined in the enriched fraction and following immunoprecipitation with an Rpt6 antibody. ATPase activity (ρmol PO4/μg protein/h) of the total fraction was lowered from 291 ± 97 to 194 ± 27 and in the immunoprecipitated fraction from 42 ± 12 to 3 ± 2 (P=0.005) in failing hearts. Conclusions: -These studies suggest that diminished 26S activity in failing human hearts may be related to impaired docking of the 19S to the 20S as a result of decreased Rpt subunit ATPase activity and α7 subunit phosphorylation.

Circ Heart Fail: 20 Mar 2013; epub ahead of print
Day SM, Divald A, Wang P, Davis F, ... Jones R, Powell SR
Circ Heart Fail: 20 Mar 2013; epub ahead of print | PMID: 23515276
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Abstract

Different Patterns of Bundle Branch Blocks and the Risk of Incident Heart Failure in the Women\'s Health Initiative (WHI) Study.

Zhang ZM, Rautaharju PM, Soliman EZ, Manson JE, ... Vitolins M, Prineas RJ
Background: -We evaluated the risk of incident heart failure (HF) associated with bundle branch blocks (BBB) in post-menopausal women. Methods and results: -Cox\'s regression was used to evaluate hazard ratios (HR) with 95% confidence intervals (CI) for HF among 65,975 participants of the Women\'s Health Initiative (WHI) study during an average follow-up of 14 years. BBB observed in 1,676 women at baseline was categorized into left, right and indetermined-type BBB (LBBB, RBBB and IVCD, respectively). Compared to women with no BBB, LBBB and IVCD were strong predictors of incident HF in multivariable-adjusted risk models (HR 3.79, CI 2.95-4.87 for LBBB and HR 3.53, CI 2.14-5.81 for IVCD). RBBB was not a significant predictor of incident HF in multivariable-adjusted risk model but the combination of RBBB and left anterior fascicular bock (RBBB&LAFB) was a strong predictor (HR 2.96, CI 1.77-4.93). QRS duration was an independent predictor of incident HF only in LBBB, with more pronounced risk at QRS ≥140 ms than below 140 ms. RNDPV was an independent predictor in both RBBB and LBBB and in addition in LBBB, QRS/STT angle and ST J-point depression in aVL were independent predictors. Conclusions: -LBBB, IVCD and RBBB combined with LAFB are strong predictors of incident HF in multivariable-adjusted risk models but RBBB is not a significant predictor, QRS duration ≥140 ms may warrant consideration in LBBB as an indication for further diagnostic evaluation for possible therapeutic and preventive action. Clinical trial registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000611.

Circ Heart Fail: 03 Jun 2013; epub ahead of print
Zhang ZM, Rautaharju PM, Soliman EZ, Manson JE, ... Vitolins M, Prineas RJ
Circ Heart Fail: 03 Jun 2013; epub ahead of print | PMID: 23729198
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Abstract

Preoperative Serum Albumin Levels Predict One-Year Postoperative Survival of Patients Undergoing Heart Transplantation.

Kato TS, Cheema F, Yang J, Kawano Y, ... Mancini DM, Schulze PC
Background: -Serum albumin concentration has been recognized as a marker of nutrition, severity of inflammation and hepatic function in patients with various chronic diseases. The purpose of this study was to investigate the impact of pre-transplant serum albumin concentration on post-transplant outcome in heart transplant (HTx) recipients. Methods and results: -Pre-operative laboratory variables including albumin concentration as well as donor-related information were obtained from 822 consecutive patients undergoing HTx at Columbia University Medical Center between 1999 and 2010. The association between pre-transplant albumin concentration and post-transplant one-year survival was analyzed. Available data from the United Network of Organ Sharing (UNOS) (n=13,671) was also analyzed to evaluate the impact of pre-operative albumin levels on post-transplant outcome. In our cohort, multivariable analysis revealed that preoperative albumin (mg/dL) [hazard ratio (HR) 0.46, p<0.0001] and pre-operative total bilirubin (mg/dL) (HR 1.26, p=0.0002) were associated with post-transplant one-year mortality. This implied that for every 1 mg/dL increase in albumin concentration, the post-transplant one-year mortality rate decreased by 54%. The Kaplan-Meier analysis based on our patients cohort and the UNOS dataset showed lower survival rate at one-year pos-transplant in patients with albumin levels≤3.5mg/dL compared to those with >3.5mg/dL (Our patients, 91.3 vs. 72.4%, p<0.0001; UNOS, 88.4 vs. 84.8%, p<0.0001). Conclusions: -Pre-transplant serum albumin concentration is a strong prognostic marker for post-transplant survival in HTx recipients.

Circ Heart Fail: 14 May 2013; epub ahead of print
Kato TS, Cheema F, Yang J, Kawano Y, ... Mancini DM, Schulze PC
Circ Heart Fail: 14 May 2013; epub ahead of print | PMID: 23674361
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Abstract

Effects of Chronic Rosiglitazone Treatment on Renal Handling of Salt and Water in Rats with Volume-Overload Congestive Heart Failure.

Goltsman I, Wang X, Lavallie ER, Diblasio-Smith EA, ... Feuerstein GZ, Winaver J
Background: -The side effects of fluid retention and edema of thiazolidinedione (TZD) class of PPARγ agonists limit their use in patients with congestive heart failure (CHF). The present study aims to explore whether chronic treatment with the TZD compound rosiglitazone (RGZ) is associated with worsening of salt and water retention in male S.D. rats with aorto-caval fistula, an experimental model of volume-overload CHF. Methods and results: -The effects of oral RGZ (30 mg/kg/day for 4 weeks) in CHF rats on plasma volume, cumulative sodium excretion, renal expression of Na(+) channels and transporters and on selected biomarkers of CHF, were compared with those in CHF rats and sham-operated controls treated with vehicle only (N=7-10). Additionally, the response to acute saline loading (3.5% of B.W.) was evaluated after 2 weeks of treatment by renal clearance methodology. Chronic RGZ treatment caused no further increase in plasma volume compared with vehicle-treated CHF rats. Moreover, no increase in renal expression of Na(+) transport-linked channels/transporters was observed in response to RGZ. Cumulative sodium excretion was enhanced in CHF rats following RGZ and by another TZD compound, pioglitazone. In response to saline loading, RGZ-treated animals displayed a higher natriuretic/diuretic response than vehicle-treated rats. Chronic RGZ treatment was not associated with any deterioration in selected biomarkers of CHF, while indices of cardiac hypertrophy and B.P. were improved. Conclusions: -Chronic RGZ treatment was not associated with worsening of fluid retention or cardiac status in rats with experimental volume-overload CHF. Rather, RGZ appeared to improve renal handling of salt and water in rats with CHF.

Circ Heart Fail: 14 Mar 2011; epub ahead of print
Goltsman I, Wang X, Lavallie ER, Diblasio-Smith EA, ... Feuerstein GZ, Winaver J
Circ Heart Fail: 14 Mar 2011; epub ahead of print | PMID: 21398416
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Abstract

The Prognostic Significance of Biomarkers in Predicting Outcome in Patients With Coronary Artery Disease and Left Ventricular Dysfunction: Results of the Biomarker Sub-Study of the Surgical Treatment for Ischemic Heart Failure (STICH) Trials.

Feldman AM, Mann DL, She L, Bristow MR, ... Velazquez EJ, Lee KL
Background: -Patients with heart failure and coronary artery disease often undergo coronary artery bypass grafting (CABG) but assessment of the risk of an adverse outcome in these patients is difficult. To evaluate the ability of biomarkers to contribute independent prognostic information in these patients, we measured levels in patients enrolled in the Biomarker Sub-studies of the Surgical Treatment for Ischemic Heart Failure (STICH) trials. Patients in STICH Hypothesis 1 were randomized to medical therapy or CABG whereas those in STICH Hypothesis 2 were randomized to CABG or CABG with left ventricular reconstruction. Methods and results: -In sub-study patients assigned to STICH Hypothesis 1 (n=606), plasma levels of sTNFR-1 and BNP were highly predictive of the primary outcome variable of mortality by univariate analysis (BNP χ(2)=40.6; p<0.0001: sTNFR-1 χ(2)=38,9; p<0.0001). When considered in the context of multivariable analysis, both BNP and sTNFR-1 contributed independent prognostic information beyond the information provided by a large array of clinical factors independent of treatment assignment. Consistent results were seen when assessing the predictive value of BNP and sTNFR-1 in patients assigned to STICH Hypothesis 2 (n=626). Both plasma levels of BNP (χ(2)=30.3) and sTNFR-1 (χ(2)=45.5) were highly predictive in univariate analysis (p<0.0001) as well as in multivariable analysis for the primary endpoint of death or cardiac hospitalization. In multivariable analysis, the prognostic information contributed by BNP (χ(2)=6.0; p=0.049) and sTNFR-1 (χ(2)=8.8; p=0.003) remained statistically significant even after accounting for other clinical information. Although the biomarkers added little discriminatory improvement to the clinical factors (increase in c-index ≤ 0.1), Net Reclassification Improvement (NRI) for the primary endpoints was 0.29 for BNP and 0.21 for sTNFR-1in the Hypothesis 1 cohort, and 0.15 for BNP and 0.30 for sTNFR-1 in the Hypothesis 2 cohort, reflecting important predictive improvement. Conclusions: -Elevated levels of sTNFR-1 and BNP are strongly associated with outcomes, independent of therapy, in two large and independent studies, thus providing important cross-validation for the prognostic importance of these two biomarkers.

Circ Heart Fail: 14 Apr 2013; epub ahead of print
Feldman AM, Mann DL, She L, Bristow MR, ... Velazquez EJ, Lee KL
Circ Heart Fail: 14 Apr 2013; epub ahead of print | PMID: 23584092
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Abstract

Sustained Cardiovascular Actions of APJ Agonism During Renin-Angiotensin System Activation and in Patients with Heart Failure.

Barnes GD, Alam S, Carter G, Pedersen CM, ... Japp A, Newby DE
Background: -To assess cardiovascular actions of APJ agonism in man during prolonged (Pyr(1))apelin-13 infusion and renin-angiotensin system activation. Methods and results: -Forty-eight volunteers and twelve patients with chronic stable heart failure attended a series of randomized placebo-controlled studies. Forearm blood flow, cardiac index, left ventricular dimensions and mean arterial pressure were measured using bilateral venous occlusion plethysmography, bioimpedance cardiography, transthoracic echocardiography and sphygmomanometry respectively during brief local (0.3-3.0 nmol/min) and systemic (30-300 nmol/min) or prolonged systemic (30nmol/min) (Pyr(1))apelin-13 infusions in the presence or absence of renin-angiotensin system activation with sodium-depletion or angiotensin II co-infusion. During sodium depletion and angiotensin II co-infusion, (Pyr(1))apelin-13 induced vasodilatation was preserved (P<0.02 for both). Systemic intravenous (Pyr(1))apelin-13 infusion increased cardiac index whilst reducing mean arterial pressure and peripheral vascular resistance index (P<0.001 for all) irrespective of sodium depletion or angiotensin II (0.5 ng/kg/min) co-infusion (P>0.05 for all). Prolonged 6-hour (Pyr(1))apelin-13 infusion caused a sustained increase in cardiac index with increased left ventricular ejection fraction in patients with chronic heart failure (ANOVA; P<0.001 for all). Conclusions: -APJ agonism has sustained cardiovascular effects in man that are preserved in the presence of renin-angiotensin system activation or heart failure. APJ agonism may hold major promise to complement current optimal medical therapy in patients with chronic heart failure. Clinical trial registration-URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00901719, NCT00901888, NCT01049646, NCT01179061.

Circ Heart Fail: 21 Mar 2013; epub ahead of print
Barnes GD, Alam S, Carter G, Pedersen CM, ... Japp A, Newby DE
Circ Heart Fail: 21 Mar 2013; epub ahead of print | PMID: 23519586
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Abstract

The Impact of Renal Tubular Damage, as Assessed by Urinary β2-microglobulin-creatinine Ratio, on Cardiac Prognosis in Patients with Chronic Heart Failure.

Otaki Y, Watanabe T, Shishido T, Takahashi H, ... Konta T, Kubota I
Background: -Renal dysfunction was reported to be closely associated with clinical outcomes in patients with chronic heart failure (CHF). Renal tubulointerstitial damage has been shown to be an important factor in the development of renal dysfunction as well as glomerular damage. However, it remains to be determined the impact of renal tubular damage on clinical outcomes in patients with CHF. Methods and results: -Urinary β2-microglobulin-creatinine ratio (UBCR) was measured in 315 patients with CHF. Renal tubular damage was defined as a UBCR ≥ 300 μg/g, as previously reported. Patients were prospectively followed for a median period of 1097 days. There were 91 cardiac events, including 16 cardiac deaths and 75 re-hospitalizations for worsening heart failure. Log10 UBCR was increased with worsening New York Heart Association (NYHA) functional class. Multivariate analysis revealed that renal tubular damage was an independent predictor of cardiac events. Kaplan-Meier analysis demonstrated that the rate of cardiac events was higher in patients with renal tubular damage compared to those without it. Patients were divided into 4 groups according to the presence of chronic kidney disease and renal tubular damage. The Cox proportional hazard analysis revealed that comorbidity of chronic kidney disease and renal tubular damage was associated with the highest risk for cardiac events compared to other groups. Conclusions: -Renal tubular damage was related to the severity of heart failure and was associated with poor outcomes in patients with CHF. Renal tubular damage could add clinical information to chronic kidney disease in patients with CHF.

Circ Heart Fail: 14 May 2013; epub ahead of print
Otaki Y, Watanabe T, Shishido T, Takahashi H, ... Konta T, Kubota I
Circ Heart Fail: 14 May 2013; epub ahead of print | PMID: 23674363
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Abstract

LVAD Therapy in Patients with Restrictive and Hypertrophic Cardiomyopathy.

Topilsky Y, Pereira NL, Shah DK, Boilson B, ... Joyce LD, Park SJ
Background: -Left ventricular assist device (LVAD) is being increasingly used in patients with end stage dilated and ischemic cardiomyopathy. There have been no clinical trials addressing the use of LVAD therapy in patients with end stage heart failure due to restrictive (RCM) or hypertrophic cardiomyopathy (HCM). The purpose of this study was therefore to analyze the outcome of LVAD therapy in these patients. Methods and results: -83 patients received continuous axial flow LVAD (Heart mate II, Thoratec, Pleasanton, CA) from February 2007 to May 2010 at our institution. We analyzed the baseline characteristics, surgical and long term impact of LVAD therapy in 8 patients with RCM or HCM, and compared their outcome to the 75 patients with dilated and ischemic cardiomyopathy. Compared to patients with ischemic or dilated cardiomyopathy, patients with RCM and HCM have significantly smaller left ventricular end diastolic dimensions (52.5±6mm vs. 68.6±8mm; p<0.0001), increased thickness of septal (16[12,19] mm vs.10[8.5,11] mm, p=0.0003) and higher left ventricular ejection fraction (21[20,36]% vs. 17[15,22]%; p=0.0009). We found no difference in early mortality (12.5% vs. 9.3%, p=0.57), or length of hospital stay (11[8,45] days vs. 18.5[12.2,27.7] days; p=0.51) between the two groups. The right atrial pressure was higher (18[15,20]mmHg vs. 12[9,15]mmHg, p=0.03), and pump flow was lower (4.3[3.8,4.5] liter vs. 5.2[4.7,5.5] liter, p=0.001) after LVAD implantation in patients with RCM and HCM. Central venous catheter related infections were more common in patients with RCM and HCM (87.5% vs. 44.5%, p=0.006). There was no difference in the total number of blood units transfused. Median (min,max) follow-up duration after LVAD implantation was 166[1,1044] days. The one-year actuarial survival rate was not different between the two groups (87.5% [95 percent confidence interval, 52.9%-97.8%] vs. 73.2 [95 percent confidence interval, 60%-85%]; p=0.77). Conclusions: -Our preliminary data shows that patients with end stage heart failure due to RCM or HCM may benefit from continuous axial flow LVAD therapy. This small study suggests that mortality is comparable with those patients who have dilated or ischemic cardiomyopathy but right heart failure, prolonged inotropic use and central venous catheter infections are more common in patients with RCM and HCM who were treated with LVAD. Because of the small numbers the differences should be interpreted cautiously and prospective clinical trials would be required to recommend this therapy for these patients as bridge to transplantation or destination treatment.

Circ Heart Fail: 09 Feb 2011; epub ahead of print
Topilsky Y, Pereira NL, Shah DK, Boilson B, ... Joyce LD, Park SJ
Circ Heart Fail: 09 Feb 2011; epub ahead of print | PMID: 21303989
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Abstract

Fish Intake and the Risk of Incident Heart Failure: The Women\'s Health Initiative.

Belin RJ, Greenland P, Martin L, Oberman A, ... Van Horn L, Lloyd-Jones D
Background: -Whether fish or the fatty acids they contain are independently associated with risk for incident heart failure (HF) among postmenopausal women is unclear. Methods and results: -The baseline Women\'s Health Initiative Observational Study (WHI-OS) cohort consisted of 93,676 women aged 50-79 of diverse ethnicity and background of which 84,493 were eligible for analyses. Intakes of baked/broiled fish, fried fish and omega-3 fatty acid (eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), α-linolenic acid (ALA)), and trans fatty acid (TFA) were determined from the WHI food frequency questionnaire. Baked/broiled fish consumption was divided into 5 frequency categories: <1/mo (referent), 1-3/mo, 1-2/wk, 3-4/wk, ≥5/wk. Fried fish intake was grouped into 3 frequency categories: <1/mo (referent), 2) 1-3/mo, and 3) ≥1/wk. Associations between fish or fatty acid intake and incident HF were determined using Cox models adjusting for HF risk factors and dietary factors. Baked/broiled fish consumption (≥5 servings/wk at baseline) was associated with a hazard ratio (HR) of 0.70 (95% CI: 0.51, 0.95) for incident HF. In contrast, fried fish consumption (≥1 serving/wk at baseline) was associated with a HR of 1.48 (95% CI: 1.19, 1.84) for incident HF. No significant associations were found between EPA+DHA, ALA, or TFA intake and incident HF. Conclusions: -Increased baked/broiled fish intake may lower HF risk, while increased fried fish intake may increase HF risk in postmenopausal women.

Circ Heart Fail: 25 May 2011; epub ahead of print
Belin RJ, Greenland P, Martin L, Oberman A, ... Van Horn L, Lloyd-Jones D
Circ Heart Fail: 25 May 2011; epub ahead of print | PMID: 21610249
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Abstract

Measurement Precision in the Optimization of Cardiac Resynchronization Therapy.

Turcott RG, Witteles RM, Wang PJ, Vagelos RH, Fowler MB, Ashley EA
Background: -Cardiac resynchronization therapy improves morbidity and mortality in appropriately selected patients. Whether atrio-ventricular (AV) and interventricular (VV) pacing interval optimization confers further clinical improvement remains unclear. A variety of techniques are used to estimate optimum AV/VV intervals, however, the precision of their estimates and the ramifications of an imprecise estimate have not previously been characterized. Methods and results: -An objective methodology for quantifying the precision of estimated optimum AV/VV intervals was developed, allowing physiologic effects to be distinguished from measurement variability. Optimization using multiple conventional techniques was conducted in individual sessions with 20 patients. Specific techniques used measures of stroke volume and dyssynchrony, and included impedance cardiography (ICG) and echocardiographic methods, specifically, aortic velocity-time integral, mitral velocity-time integral, A-wave truncation, and septal-posterior wall motion delay. Echocardiographic methods yielded statistically insignificant data in the majority of patients (62-86%). In contrast, ICG yielded statistically significant results in 84% and 75% of patients for AV and VV interval optimization, respectively. Individual cases demonstrate that accepting a plausible but statistically insignificant estimated optimum AV or VV interval can result in worse cardiac function than default values. Conclusions: -Consideration of statistical significance is critical for validating clinical optimization data in individual patients and for comparing competing optimization techniques. Accepting an estimated optimum without knowledge of its precision can result in worse cardiac function than default settings as well as a misinterpretation of observed changes over time. In the present study only ICG yielded statistically significant AV/VV interval optimization data in the majority of patients.

Circ Heart Fail: 23 Feb 2010; epub ahead of print
Turcott RG, Witteles RM, Wang PJ, Vagelos RH, Fowler MB, Ashley EA
Circ Heart Fail: 23 Feb 2010; epub ahead of print | PMID: 20176716
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Abstract

Left Ventricular Systolic Dysfunction, Heart Failure and the Risk of Stroke and Systemic Embolism in Patients with Atrial Fibrillation: Insights from the ARISTOTLE Trial.

McMurray JJ, Ezekowitz JA, Lewis BS, Gersh BJ, ... Wallentin L, Granger CB
Background: -We examined the risk of stroke or systemic embolism (SSE) conferred by heart failure (HF) and left ventricular systolic dysfunction (LVSD) in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (AF)Trial (ARISTOTLE), as well as the effect of apixaban versus warfarin. Methods and results: -The risk of a number of outcomes including the composite of SSE or death (to take account of competing risks) and composite of SSE, major bleeding or death ("net clinical benefit") were calculated in 3 patient groups: 1) No HF/no LVSD (n=8728) 2) HF/no LVSD (n=3207) and 3) LVSD with/without symptomatic HF (n=2736). The rate of both outcomes was highest in patients with LVSD (SSE or death 8.06; SSE, major bleeding or death 10.46 per 100 patient-years), intermediate for HF but preserved LV systolic function (5.32; 7.24) and lowest in patients without HF or LVSD (1.54; 5.27); each comparison p<0.0001. Each outcome was less frequent in patients treated with apixaban: in all ARISTOTLE patients, the apixaban/warfarin hazard ratio for SSE or death 0.89 (95% CI 0.81,0.98) p=0.02; for SSE, major bleed or death it was 0.85 (0.78,0.92); p<0.001. There was no heterogeneity of treatment-effect across the 3 groups. Conclusions: -Patients with LVSD (with/without HF) had a higher risk of SSE or death (but similar rate of SSE) compared with patients with HF but preserved LV systolic function; both had a greater risk than patients without either HF or LVSD. Apixaban reduced the risk of both outcomes more than warfarin in all 3 patient groups. Clinical trial registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.

Circ Heart Fail: 10 Apr 2013; epub ahead of print
McMurray JJ, Ezekowitz JA, Lewis BS, Gersh BJ, ... Wallentin L, Granger CB
Circ Heart Fail: 10 Apr 2013; epub ahead of print | PMID: 23575255
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Abstract

Activities Worth Living For: A Call to Action Beyond Prognosis.

Lewis EF
Given the advances in the treatment options for chronic heart failure (CHF), the estimated 5 million people in the United States living with CHF have realized gradual improvements in their median life expectancy (1). Expectantly, there has been an increased focus on how well these patients live in addition to their longevity. The measurements of the wellness of patients include both patient-reported outcome tools and provider-based assessments. The model that links disease burden to these patient-centered outcome measures is well-established in literature (2) and serves as the basis for novel interventions to improve these outcomes. Activities of daily living (ADLs) often involve many factors that are intermediate variables in the determinants of health-related quality of life (HRQL) and are often taken for granted when not evaluated in the context of disease burden. Despite these ADLs often being differentially influenced by the specific disease and the associated symptoms, patients may have impairments in their ability to perform due to factors unrelated to the specific disease. Although ADLs are important in clinical management, the focus on measurements as well as interventions to improve these important tasks are often assessed by physical and occupational therapist, nurses, social workers, and care coordinators with less attention by physicians.

Circ Heart Fail: 25 Feb 2015; epub ahead of print
Lewis EF
Circ Heart Fail: 25 Feb 2015; epub ahead of print | PMID: 25717058
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Abstract

Characteristics and Outcome following Hospitalization for Acute Right Heart Failure in Patients with Pulmonary Arterial Hypertension.

Haddad F, Peterson T, Fuh E, Kudelko KT, ... Doyle RL, Zamanian RT
Background: -While much is known about risk factors for poor outcome in patients hospitalized with acute left heart failure, much less is known about the syndrome of acute right heart failure. A better understanding of factors associated with poor outcome following hospitalization for acute right heart failure may help guide care of patients with pulmonary arterial hypertension (PAH). Methods and results: -Using Stanford Hospital\'s pulmonary hypertension database, we identified consecutive acute heart failure hospitalizations in patients with PAH. Acute right heart failure was defined as new onset or rapidly worsening right heart failure requiring urgent inpatient therapy. We used longitudinal regression analysis with the generalized estimating equations method to identify factors associated with an increased likelihood of 90-day mortality or urgent transplantation. From June 1999 to September 2009, 119 patients with PAH were hospitalized for acute right heart failure (207 episodes). Death or urgent transplantation occurred in 34 patients (18% of hospitalizations) by 90 days of admission. Multivariable analysis identified higher respiratory rate on admission (respiratory rate > 20 breaths per minute; odds ratio (OR)=3.4, 95% confidence interval (CI)=1.5-7.8, renal dysfunction on admission (glomerular filtration rate < 45mL/min/1.73m(2); OR=2.7, 95% CI=1.2-6.3), hyponatremia (serum sodium ≤ 136 mEq/L, OR= 3.6, 95% CI =1.7-7.9) and tricuspid regurgitation severity (OR=2.5 per grade, 95% CI =1.2-5.5) as independent factors associated with an increased likelihood of death or urgent transplantation. Conclusions: -These results highlight the high mortality following hospitalizations for acute right heart failure in patients with PAH. Factors identifiable within hours of hospitalization may help predict the likelihood of death or need for urgent transplantation in patients with PAH.

Circ Heart Fail: 12 Sep 2011; epub ahead of print
Haddad F, Peterson T, Fuh E, Kudelko KT, ... Doyle RL, Zamanian RT
Circ Heart Fail: 12 Sep 2011; epub ahead of print | PMID: 21908586
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Abstract

Depression, Healthcare Utilization, and Death in Heart Failure: A Community Study.

Moraska AR, Chamberlain AM, Shah ND, Vickers KS, ... Redfield MM, Roger VL
Background: -The increasing prevalence of heart failure (HF) and high associated costs have spurred investigation of factors leading to adverse outcomes in HF patients. Studies to date report inconsistent evidence regarding the link between depression and outcomes with only limited data on emergency department (ED) and outpatient visits. Methods and results: -Olmsted, Dodge, and Fillmore county, MN residents with HF were prospectively recruited between October 2007 and December 2010, and completed a one-time 9-item Patient Health Questionnaire (PHQ-9) for depression categorized as: none-minimal (PHQ-9 score 0-4), mild (5-9), or moderate-severe (≥10). Andersen-Gill models were used to determine if depression predicted hospitalizations and ED visits while negative binomial regression models explored the association of depression with outpatient visits. Cox proportional hazards regression characterized the relationship between depression and all-cause mortality. Among 402 HF patients (mean age 73±13, 58% male), 15% had moderate-severe depression, 26% mild, and 59% none-minimal. Over a mean follow-up of 1.6 years, 781 hospitalizations, 1000 ED visits, 15,515 outpatient visits, and 74 deaths occurred. After adjustment, moderate-severe depression was associated with nearly a 2-fold increased risk of hospitalization (HR 1.79, 95% CI 1.30-2.47) and ED visits (HR 1.83, 95% CI 1.34-2.50), a modest increase in outpatient visits (RR 1.20, 95% CI 1.00-1.45), and a 4-fold increase in all-cause mortality (HR 4.06, 95% CI 2.35-7.01). Conclusions: -In this prospective cohort study, depression independently predicted an increase in the use of healthcare resources and mortality. Greater recognition and management of depression in HF may optimize clinical outcomes and resource utilization.

Circ Heart Fail: 19 Mar 2013; epub ahead of print
Moraska AR, Chamberlain AM, Shah ND, Vickers KS, ... Redfield MM, Roger VL
Circ Heart Fail: 19 Mar 2013; epub ahead of print | PMID: 23512984
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Abstract

Application of an Exercise Intervention on the Evolution of Diastolic Dysfunction in Patients with Diabetes Mellitus: Efficacy and Effectiveness.

Hare JL, Hordern MD, Leano R, Stanton T, Prins JB, Marwick TH
Background: -Diastolic dysfunction (DD) is associated with adverse cardiovascular outcomes. We sought to study the impact of an exercise-lifestyle intervention upon evolution of DD in patients with type 2 diabetes mellitus (T2DM), and prospectively investigate the clinical correlates of DD progression. Methods and results: -223 outpatients with T2DM were randomized to supervised exercise-lifestyle intervention (initial gym based program and lifestyle/diet advice followed by telephone-guided supervision) or usual care. Patients underwent echocardiographic assessment of diastolic function, metabolic and clinical evaluation at baseline and 3 years. Changes in prevalence and evolution of DD were assessed, and correlations sought with clinical and metabolic variables. Diastolic dysfunction was present in 50% of patients at baseline and 54% at 3 years, with no difference between usual care and intervention groups (60% vs 48%, p=0.10). Abnormal DD at final visit was independently associated with older age and a decrease in peak VO(2) over time (p<0.05). There was no impact on glycemic control or exercise capacity. In a sub-analysis restricted to those who finished the full 3-year follow-up, control subjects were independently associated with DD at 3 years (β=0.90, OR 2.46, p=0.034), with the only other independent correlate being older age (β=0.05, OR 1.06, p=0.019). Conclusions: -Despite being efficacious is the subgroup who completed 3 years of exercise-based lifestyle intervention, randomization to this program was not effective in reducing progression of subclinical diastolic dysfunction in patients with type 2 diabetes mellitus. This may reflect the recognized difficulty of adherence to prolonged exercise intervention. Clinical trial registration-URL: http://www.anzctr.org.au. Unique identifier: ACTRN12607000060448.

Circ Heart Fail: 17 May 2011; epub ahead of print
Hare JL, Hordern MD, Leano R, Stanton T, Prins JB, Marwick TH
Circ Heart Fail: 17 May 2011; epub ahead of print | PMID: 21576281
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This program is still in alpha version.