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Supplemental Digital Content is available in the text., Background: Sodium-glucose cotransporter 2 inhibitors reduce the risk of heart failure hospitalization and cardiovascular death in patients with heart failure and reduced ejection fraction (HFrEF). However, their effects on cardiac structure and function in HFrEF are uncertain. Methods: We designed a multicenter, randomized, double-blind, placebo-controlled trial (the SUGAR-DM-HF trial [Studies of Empagliflozin and Its Cardiovascular, Renal and Metabolic Effects in Patients With Diabetes Mellitus, or Prediabetes, and Heart Failure]) to investigate the cardiac effects of empagliflozin in patients in New York Heart Association functional class II to IV with a left ventricular (LV) ejection fraction ≤40% and type 2 diabetes or prediabetes. Patients were randomly assigned 1:1 to empagliflozin 10 mg once daily or placebo, stratified by age (

Drug interactions between antiretroviral therapy and anticoagulant medications are of particular concern given that ≈50% of the current HIV population is >50 years of age. Moreover, HIV infection is characterized by a hypercoaguable state and premature immunologic aging, in which thromboembolic events may be as much as 10 times more prevalent than in the general population across all age spectra.1 Dabigatran was the first direct oral anticoagulant approved by the US Food & Drug Administration and is the only direct oral anticoagulant with a US Food & Drug Administration -approved specific reversal agent, idarucizumab. Unlike warfarin and many other direct oral anticoagulants, dabigatran is not a substrate, inhibitor, or inducer of cytochrome P450 metabolic enzymes. However, dabigatran is a substrate of Permeability-glycoprotein (P-gp) and renal multidrug and toxin extrusion-1 transporters. Cobicistat is a US Food & Drug Administration -approved antiretroviral-boosting agent that is coformulated with numerous fixed-dose combination antiretroviral products because of its inhibitory effects on cytochrome P450 3A4. Currently, ≈40% of all treatment-naive patients with HIV in the United States are initiated on a cobicistat-boosted antiretroviral regimen. In addition to cytochrome P450 3A4, cobicistat is also an inhibitor of both P-gp and multidrug and toxin extrusion-1 transporters.2 Thus, this study aimed to determine whether the …

Introduction: Atrial fibrillation (AF) is the most common arrhythmia and is associated with significant morbidity and mortality. Despite having a higher burden of traditional AF risk factors, African American and Hispanic minorities have a lower incidence of AF when compared to non-Hispanic Whites, referred to as the “racial paradox.” Hypothesis: We investigated if socioeconomic status (SES) could be an explanatory factor for the “racial paradox.” Methods: An ECG/EMR database from a tertiary-care center in New York State was interrogated for individuals free of AF for development of subsequent AF from 2000-2013. SES was assessed per zip code via a log composite of six measures Z-scored to the New York State average (income; value of housing unit; percentage of receiving interest/dividend/rental income; education; percentage completed college; individuals in professional positions). SES was reclassified into decile groups (1 lowest and 10 highest). The Log-Rank test was used to determine difference in survival times to develop AF by race/ethnicity stratified by SES decile. Cox regression analysis controlling for all baseline differences was used to estimate the independent predictive ability of SES for AF. P-trend was calculated by race/ethnicity to determine if there was a trend by SES decile to develop AF. Results: We identified 48,631 persons (43% Hispanic, 37% African Americans and 20% non-Hispanic White, mean age 59 years, mean follow-up of 3.2 years) of which 4,556 AF cases occurred. Hispanics and African Americans had lower AF risk than Whites in all SES deciles (p-value < 0.001 by Log Rank Test). Higher SES was borderline associated with lower AF risk (HR=0.990, 95% CI 0.980-1.001, p=0.061). P-trend analysis was not significant by any race/ethnic group by SES deciles for AF (Figure 1). Conclusions: Our study suggests that non-Hispanic Whites are at higher risk for AF compared to non-Whites, and this is independent of socioeconomic status.

Background— The role of C-reactive protein (CRP) in heart failure is not well studied. We assessed the prognostic value of CRP in patients randomized in Val-HeFT (Valsartan Heart Failure Trial) and studied changes in CRP that were associated with valsartan. Methods and Results— Characteristics of patients with baseline CRP levels above and below the median value were compared. Univariable and multivariable Cox proportional hazards regression models were used to examine the relationship of CRP to mortality and morbidity. Interactions were tested to determine whether differences in CRP changes from baseline to 4 and 12 months between groups randomly assigned to valsartan or placebo depended on baseline ACE inhibitor use. Median plasma CRP was 3.23 mg/L (interquartile range 1.42 to 7.56 mg/L), which is higher than in the general population. Patients with CRP above the median had features of more severe heart failure than those with CRP levels below the median. The cumulative likelihood of death and first morbid event increased with increasing quartile of CRP. Relative to the lowest CRP quartile, the risk of mortality (hazard ratio 1.51, 95% CI 1.2 to 1.9) and first morbid event (hazard ratio 1.53, 95% CI 1.28 to 1.84) was increased in the highest CRP quartile in multivariable models. CRP added incremental prognostic information to that provided by brain natriuretic peptide alone. CRP did not change significantly over time in the placebo group; however, after 12 months, valsartan was associated with a decrease in CRP in patients not receiving ACE inhibitors but not in those receiving ACE inhibitors at 12 months. Conclusions— CRP is increased in heart failure. Higher levels are associated with features of more severe heart failure and are independently associated with mortality and morbidity. The ability of treatments to reduce CRP levels and the prognostic importance of reducing CRP require further study.

I would like to begin by expressing my deep appreciation to the Clinical Council for honoring me this year with the annual James B. Herrick Award. As a longstanding maverick cardiovascular investigator, I recognize the unfortunate fate of many mavericks who more often face sanction than accolades, and I am therefore particularly grateful that the Council has seen fit to honor me for a lifetime of effort that has often challenged traditional thinking. My maverick attitudes surfaced early in my training, when I began a cardiovascular research fellowship at Georgetown University after completing a tour of duty in the public health service. Having initiated my research career in clinical and animal hemodynamic studies under the tutelage of Dr Edward Freis, I became focused on physiological mechanisms. During clinical rounds with Dr Proctor Harvey, a group of us young fellows surrounded the bed of a man with heart failure and watched as Dr Harvey carefully palpated the radial pulse and announced the presence of pulsus alternans. Each fellow in turn took the patient’s wrist and nodded agreement with the finding. I frankly was unable to detect an alteration in the strength of the pulsation, and my protestation was met by the comment that I needed to educate my fingers. Unwilling to accept this simple explanation for my perceived deficiency, I went to my laboratory, brought a transducer and recorder to the bedside, and proceeded to puncture the radial artery to record the arterial pressure. The long recording revealed no alteration in systolic or pulse pressure but only the usual respiratory pressure variation. I excitedly brought the tracing to Dr Harvey, who calmly announced to me that his fingers were more sensitive than my transducer. That early experience convinced me that there was much to learn about clinical pathophysiology that might be …

Background— Hypertrophic cardiomyopathy (HCM) has a diverse clinical spectrum that often includes progressive heart failure symptoms and disability. Assessment of symptom severity may be highly subjective, encumbered by the heterogeneous clinical presentation. Plasma B-type natriuretic peptide (BNP) has been used widely as an objective marker for heart failure severity and outcome, predominantly in coronary heart disease with ventricular dilatation and systolic dysfunction. Methods and Results— We prospectively assessed plasma BNP as a quantitative clinical marker of heart failure severity in 107 consecutive HCM patients. BNP showed a statistically significant relationship to magnitude of functional limitation, assessed by New York Heart Association (NYHA) functional class: I, 136±159 pg/mL; II, 338±439 pg/mL; and III/IV, 481±334 pg/mL ( P P =0.0001). BNP ≥200 pg/mL was the most reliable predictor of heart failure symptoms, with positive and negative predictive values of 63% and 79%, respectively. BNP power in distinguishing patients with or without heart failure symptoms was less than that for differentiating between no (or only mild) and severe symptoms (area under receiver operating characteristic curve=0.75 and 0.83, respectively). Conclusions— Plasma BNP is independently related to the presence and magnitude of heart failure symptoms in patients with HCM. As a clinical marker for heart failure, BNP is limited by considerable overlap in values between categories of heart failure severity as well as confounding variables of left ventricular wall thickness and age.

Background— Aldosterone has been implicated in the progression of heart failure. The Valsartan Heart Failure Trial (Val-HeFT) provided the first opportunity to examine the long-term effects of an angiotensin receptor blocker on plasma aldosterone levels in patients with NYHA class II through IV heart failure. Methods and Results— Plasma aldosterone was measured by radioimmunoassay in core laboratories at baseline and during follow-up in patients assigned to valsartan at a target dose of 160 mg twice daily or placebo. In the placebo group, aldosterone (baseline, 150±160 pg/mL, mean±SD; n=2025) increased at 4, 12, and 24 months. In the valsartan group, aldosterone (baseline, 137±124 pg/mL, mean±SD; n=2023) decreased at 4 months and remained suppressed for up to 2 years. At end point (last measurement in each patient), mean aldosterone increased by 17.8±3.0 pg/mL (SEM) (11.9%) in the placebo group and decreased by 23.8±3.0 pg/mL (SEM) (−17.4%) in the valsartan group ( P Conclusions— Valsartan added to background therapy for heart failure produces sustained reduction in plasma aldosterone, consistent with the observed significant reduction in the combined mortality/morbidity end point. A similar reduction in all subgroups based on ACE-I or BB therapy, despite differing clinical outcomes in these subgroups, suggests that aldosterone plasma levels may not be a critical marker of the progression of heart failure.

Background— Neurohormones are considered markers of heart failure progression. We examined whether changes in brain natriuretic peptide (BNP) and norepinephrine (NE) over time are associated with corresponding changes in mortality and morbidity in the Valsartan Heart Failure Trial. Methods and Results— Plasma BNP and NE were measured before randomization and during follow-up in ≈4300 patients in the Valsartan Heart Failure Trial. The relation between baseline BNP and NE and all-cause mortality and first morbid event (M&M) was analyzed in subgroups, with values above and below the median, and by quartiles. The change and percent change from baseline to 4 and 12 months in BNP and NE were also analyzed by quartiles for subsequent M&M. Risk ratios for M&M were calculated using a Cox proportional hazard model. Risk ratio of M&M for patients with baseline BNP or NE above the median was significantly higher than that for patients with values below the median. Baseline BNP and NE in quartiles also showed a quartile-dependent increase in M&M. BNP had a stronger association with M&M than NE. Patients with the greatest percent decrease in BNP and NE from baseline to 4 and 12 months had the lowest whereas patients with greatest percent increase in BNP and NE had the highest M&M. Conclusions— Not only are plasma BNP and NE important predictors of heart failure M&M, but changes in these neurohormones over time are associated with corresponding changes in M&M. These data further reinforce their role as significant surrogate markers in HF and underscore the importance of including their measurement in HF trials.

Background: Atrial fibrillation (AF) and isthmus dependent atrial flutter (AFL) are two separate entities that in many patients coexist. We sought to investigate whether AF inducibility (spontaneous or drug induced) during isthmus AFL ablation predicted the occurrence of AF at follow up after successful AFL ablation. Methods: Two hundred seventy three consecutive patients with isthmus dependent AFL undergoing ablation of AFL at our institution were enrolled in this study. 119 (43%) patients were excluded since they had evidence of AF prior to AFL ablation. Univariate and multivariate analyses were performed. Results: A total of 154 patients (male: 72%, age: 61 ±13) with AFL and without history of AF composed our patient population. All patients underwent successful AFL ablation. During ablation, AF was induced in 28 (18%) patients. After a mean follow up of 34 ± 23.5 months a total of 50 (32%) experienced AF. Univariate and multivariate analyses showed that only age and AF inducibility during AFL ablation were predictors of AF. Univariate analysis (age: p=0.038 and inducible AF p=0.032 and multivariate analysis (age: p=0.011 inducible AF: p=0.016) ) with and adjusted odds ratio of 3.3 [95% CI (1.250-8.676)] (Table 1). A total of 169 (62%) patients experienced AF before or after AFL ablation. Conclusion: AF inducibility in patients undergoing isthmus dependent AFL without history of AF is a strong predictor of AF recurrence. This has an important clinical relevance on anticoagulation management of these patients.

Introduction: LFLG severe AS (stroke volume index Hypothesis: Patients with LFLG severe AS undergoing TAVR will have a higher rate of adverse clinical outcomes. Methods: In a retrospective single center registry, we analyzed the clinical, 2D doppler-echocardiographic and outcome data in consecutive patients who underwent TAVR with the Edwards Sapien transcatheter aortic valve for symptomatic severe AS at our tertiary care hospital from March 2012 to April 2014. Patients with LFLG were compared to non-LFLG patients. Background medical data, clinical endpoints (defined by the Valve Academic Research Consortium-2), length of stay (LOS), readmissions and mortality, were compared between the two groups. Wilcoxon rank-sum and Fisher’s exact tests were used to evaluate the hypothesis. Results: LFLG was found in 66 (32%) out of 206 patients. Baseline characteristics were comparable between the LFLG and non-LFLG group, except significant difference in STS scores (12.1±8 vs. 9.9±8, p=0.011), prior aortic valve surgery (16.7% vs. 6.4%, p=0.041) and atrial fibrillation/flutter (57.6% vs. 29.3% (p Conclusions: LFLG patients had higher co-morbidities but comparable peri-procedural complications and short-term mortality. However this group was associated with longer hospitalizations and higher 1-year all-cause-mortality following TAVR. Further studies are needed to fully define outcomes in LFLG patients.

Background —ACE inhibitors may not adequately suppress deleterious levels of angiotensin II in patients with heart failure. An angiotensin receptor blocker added to an ACE inhibitor may exert additional beneficial effects. Methods and Results —Eighty-three symptomatic stable patients with chronic heart failure receiving long-term ACE inhibitor therapy were randomly assigned to double-blind treatment with valsartan 80 mg BID, valsartan 160 mg BID, or placebo while receiving their usual ACE inhibitor therapy. Studies were performed before and after the first dose of the test drug and again after 4 weeks of therapy. A single dose of lisinopril was administered during study days to ensure sustained ACE inhibition. Compared with placebo, the first dose of valsartan 160 mg resulted in a significantly greater reduction in pulmonary capillary wedge pressure at 3, 4, and 8 hours and during the prespecified 4- to 8-hour interval after the dose and in systolic blood pressure at 2, 3, 6, 8, and 12 hours and 4 to 8 hours after the dose. A pressure reduction from valsartan 80 mg did not achieve statistical significance. After 4 weeks of therapy, net reductions in 0-hour trough pulmonary capillary wedge pressure (−4.3 mm Hg; P =0.16), pulmonary artery diastolic pressure (−4.7 mm Hg; P =0.013), and systolic blood pressure (−6.8 mm Hg; P =0.013) were observed in the valsartan 160 mg group compared with placebo. After 4 weeks of therapy, plasma aldosterone was reduced by valsartan 80 mg BID (−52.1 pg/mL; P =0.001) and 160 mg BID (−47.8 pg/mL; P P =0.10). Seventy-four of the 83 patients completed the trial. Conclusions —Physiologically active levels of angiotensin II persist during standard long-term ACE inhibitor therapy.

Most cardiovascular morbid events are the consequence of a progressive vascular disease called atherosclerosis. This disease begins at an early age, probably initially with a defect or injury of the arterial endothelial protective function, and progresses with structural remodeling in the microcirculation and cellular and lipid accumulation in conduit arteries complicated by calcification, plaque formation, and, ultimately, plaque rupture as a precipitating factor for clot formation and acute morbid events.1 The rate of progression of this process is highly variable but may extend over many decades. Furthermore, aging changes, pressure effects, and atherosclerotic changes become inextricably intertwined. Articles pp 657 and 664 Because it is now possible to slow progression of this vascular disease with a number of pharmacological agents and possibly with lifestyle alterations, the discovery of markers that can identify the disease in asymptomatic individuals could facilitate appropriate intervention. The wall of the artery is the primary site of the disease process and has therefore become an attractive target for demonstrating functional or structural alterations that may precede the morbid events. Noninvasive assessment of the arterial vasculature suitable for screening has been practiced since the development of the blood pressure cuff. Unfortunately, the ease of blood pressure measurement and the demonstration of its correlation with morbid events inhibited for many years the development of methods to more directly assess the arteries. Recently, there has been growing recognition that the disease of interest is in the arteries and that elevated blood pressure, although it may serve as a crude surrogate for arterial disease, is neither a sensitive nor a specific guide to its presence.2 Therefore, a number of noninvasive methods have been introduced to gain better insight into the abnormalities in the wall of the artery that can define the atherosclerotic process. It is important to begin …

Background Despite therapy with diuretics, ACE inhibitors and digoxin morbidity and mortality in heart failure remain high and might respond favorably to an additional vasodilator. Methods and Results Male patients (n=450) with chronic heart failure (cardiac dysfunction and impaired exercise performance) on optimal current therapy (97% enalapril, 89% diuretics) were randomly assigned to double-blind treatment with felodipine extended release (5 mg BID) or placebo for 3 to 39 months (average, 18 months). Felodipine significantly reduced blood pressure and, at 3 months, increased ejection fraction (2.1% versus −0.1% units in the placebo group, P =.001) and reduced plasma atrial natriuretic peptide levels (−2.9 versus 26.9 pg/mL in the placebo group, P =.01) but did not improve exercise tolerance, quality of life, or the need for hospitalization. During long-term follow-up, the favorable effects on ejection fraction and atrial peptide did not persist, but felodipine prevented worsening exercise tolerance and quality of life. In the felodipine and placebo groups, mortality (13.8% versus 12.8%, respectively) and hospitalization (43% versus 42%) rates were similar, and a higher incidence of peripheral edema was the only apparent side effect of felodipine therapy. Conclusions Felodipine exerts a well-tolerated additional sustained vasodilator effect in patients with heart failure treated with enalapril, but the only possible long-term benefit was a trend for better exercise tolerance and less depression of quality of life in the second year of treatment. The drug appears to be safe but not clearly efficacious in patients with heart failure.

The SEP identified priorities to support in future basic and clinical research and pointed out directions likely to result in advances against heart failure. The list is not intended to be all-encompassing and does not address, for example, exciting lines of work already under way. Rather, the recommendations are designed to point out gaps in current knowledge not being adequately addressed and highly promising new directions. Although the incidence of heart failure continues to grow, emerging lines of research provide hope that research advances will eventually lead to more effective treatment and ultimately to prevention. This research will be well served by bringing the latest multidisciplinary approaches and the best investigators to focus on the problems of heart failure. It is hoped the efforts of distinguished expert entities such as the task force and SEP will be a useful guide in addressing the needs of the biomedical community and assisting in its success.

The ultimate goal of all cardiovascular clinical research should be to reduce the morbidity and mortality from cardiovascular diseases at an acceptable cost. In no area of medicine has clinical research led to a greater change in medical care than in the management of acute myocardial infarction (AMI). We now try to accomplish early coronary reperfusion in all ST-elevation MIs and administer a combination of drugs in the postinfarction period to halt or slow the progressive remodeling process that leads to heart failure and shortened survival.1 Clinical trials have documented the dramatic efficacy of these therapeutic interventions on morbidity and mortality.2–5 Article see p 2577 The old nontherapeutic approach was not so long ago. During my internship in Boston in 1956, my first admission was a middle-aged man with an acute transmural anterior wall MI. After ministering to him for his 4-week hospital stay, which was mandatory in those days, he went home stable, only to return in 6 months with fulminant heart failure that took his life. What happened to him in that 6 months was mysterious to me, as well as to my Harvard attending physicians, who viewed the patient’s course as a rather uninteresting response to heart damage. It was 30 years before the concept of structural remodeling became recognized and effectively treated.6 Chin et al7 in this issue of Circulation explore changes in the course of patients like mine as a consequence of our new aggressive therapeutic approach. They used a complete national sample of AMI hospitalizations in nearly 3 million …

Background We tested the hypothesis that carvedilol inhibits clinical progression in patients with mildly symptomatic heart failure due to left ventricular (LV) systolic dysfunction. Methods and Results Patients (n=366) who had mildly symptomatic heart failure with an LV ejection fraction (LVEF) ≤0.35, had minimal functional impairment (defined as the ability to walk 450 to 550 m on a 6-minute walk test), and were receiving optimal standard therapy, including ACE inhibitors, were randomized double-blind to carvedilol (n=232) or placebo (n=134) and followed up for 12 months. The primary end point was clinical progression, defined as death due to heart failure, hospitalization for heart failure, or a sustained increase in heart failure medications. Clinical progression of heart failure occurred in 21% of placebo patients and 11% of carvedilol patients, reflecting a 48% ( P =.008) reduction in the primary end point of heart failure progression (relative risk, 0.52; CI, 0.32 to 0.85). This effect of carvedilol was not influenced by sex, age, race, cause of heart failure, or baseline LVEF. Carvedilol also significantly improved several secondary end points, including LVEF, heart failure score, NYHA functional class, and the physician and patient global assessments. Carvedilol reduced all-cause mortality but had no effects on the Minnesota Living With Heart Failure scale, the distance walked in 9 minutes on a self-powered treadmill, or cardiothoracic index. The drug was well tolerated. Conclusions Carvedilol, when added to standard therapy, including an ACE inhibitor, reduces clinical progression in patients who are only mildly symptomatic with well-compensated heart failure.

The syndrome of heart failure has traditionally been viewed as a functional disorder precipitated by impaired left ventricular pump performance. The classification into systolic and diastolic dysfunction has emphasized the functional distinction between abnormalities in contraction and relaxation. Recently, however, attention has been directed toward the possibility that the systolic dysfunction, which has been thought to be related to contractile failure, could be a consequence of a structural increase in ventricular chamber volume. This construct would revise the conventional view—contractile failure leads to chamber dilatation—with a more anatomic basis for heart failure: Chamber dilatation occurs as an early response that results in the reduced wall motion that is mandated to generate a normal stroke volume from a large ventricular end-diastolic volume. This structural alteration is not necessarily related to the underlying etiological cardiac pathology but rather represents an intrinsic morphological change that progresses over time in response to an initiating event. The term “remodeling” often is used to address these structural changes and may be best defined as a change in chamber volume and shape not related to a preload-mediated increase in sarcomere length. In this issue of Circulation , Greenberg and his SOLVD colleagues1 revisit the remodeling issue in chronic heart failure with echocardiographic data collected in the long-term trial of enalapril versus placebo in both symptomatic and asymptomatic patients with left ventricular remodeling. Patients were selected for this study on the basis of an ejection fraction of ≤35%. At the time the study was designed, this low ejection fraction was defined as systolic dysfunction. The implication of that designation is that an impairment of myocardial shortening was the primary abnormality. A more contemporary hypothesis, based on the concept of left ventricular remodeling, is that the low ejection fraction reflects in part a primary increase in chamber volume …

Background Converting enzyme inhibitor (CEI) therapy, but not angiotensin II subtype I receptor blockade, has been shown to attenuate left ventricular remodeling in the dog after transmyocardial direct current (DC) shock. The purpose of this study was to address the importance of preservation of bradykinin to the antiremodeling effect of CEI treatment in this model. Methods and Results Twenty-four hours after DC shock, adult mongrel dogs were assigned to one of three groups: a control group; a group treated with ramipril 10 mg BID; and a group treated with ramipril 10 mg BID along with a continuous subcutaneous infusion of HOE 140, a bradykinin antagonist. To assess change in left and right ventricular structure, a magnetic resonance imaging (MRI) study was performed 4 weeks after DC shock and compared with a baseline MRI study performed before DC shock. The increase in left ventricular mass (mean±SEM) in the control group was similar to that observed in the CEI–HOE 140 group (+0.73±0.19 versus +0.75±0.18 g/kg, P =NS), but both were greater than the change in mass in the ramipril group (−0.48±0.13 g/kg, P =.004 and P =.0005, respectively). No significant change occurred in left ventricular volume or right ventricular structure in any group. Mean arterial pressure was reduced by ramipril compared with the control group (−8±2 versus +7±2 mm Hg, P =.03), and this effect was not blunted by the addition of HOE 140 (−7±3 mm Hg). Conclusions Prevention by ramipril of the early increase in left ventricular mass in the DC shock model appears to be related to the preservation of bradykinin.

Background— Cardiac troponins are emerging as important prognostic markers in chronic cardiovascular conditions like stable coronary artery disease or chronic heart failure (HF). Less is known about the relation between serial measurements of high-sensitivity cardiac troponin T (hs-cTnT) and future events in HF. We determined the association between changes over time in hs-cTnT and outcome in patients with chronic HF. Methods and Results— We analyzed 5284 patients with chronic HF from 2 independent randomized clinical trials, the Valsartan Heart Failure Trial (Val-HeFT) (n=4053) and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca–Heart Failure (GISSI-HF) trial (n=1231). hs-cTnT was measured at randomization and after 3 months (GISSI-HF) or 4 months of follow-up (Val-HeFT). The association between changes over time of hs-cTnT and various outcomes was tested in multivariable models. In both studies, increases in hs-cTnT levels over time were associated with age, diabetes mellitus, worsening of renal function (reduction in estimated glomerular filtration rate), and baseline and increases in N-terminal pro-brain natriuretic peptide concentrations. Increases in hs-cTnT concentrations were associated with all-cause mortality (incidence rates, 8.19 [7.51–8.88] and 6.79 [5.98–7.61] per 100 person-years in Val-HeFT and GISSI-HF, respectively, with hazard ratios [95% confidence intervals] of 1.59 [1.39–1.82] and 1.88 [1.50–2.35]) after adjustment for conventional risk factors and baseline levels of hs-cTnT and N-terminal pro-brain natriuretic peptide. Changes in hs-cTnT concentration modestly improved prognostic discrimination beyond baseline values for fatal outcomes only. Conclusions— Despite very low circulating concentrations, changes in hs-cTnT concentrations over time are robust predictors of future cardiovascular events in patients with chronic HF but add limited prognostic discrimination. Clinical Trial Registration— http://www.clinicaltrials.gov . Unique identifier: NCT00336336.

Background— Growth-differentiation factor-15 (GDF-15) is emerging as a prognostic biomarker in patients with coronary artery disease. Little is known about GDF-15 as a biomarker in patients with heart failure. Methods and Results— The circulating concentration of GDF-15 was measured at baseline (n=1734) and at 12 months (n=1517) in patients randomized in the Valsartan Heart Failure Trial (Val-HeFT). GDF-15 levels at baseline ranged from 259 to 25 637 ng/L and were abnormally high (>1200 ng/L) in 85% of patients. Higher levels were associated with features of worse heart failure and biomarkers of neurohormonal activation, inflammation, myocyte injury, and renal dysfunction. Baseline GDF-15 levels (per 100 ng/L) were associated with the risks of mortality (hazard ratio, 1.017; 95% confidence interval, 1.014 to 1.019; P P P =0.02) but not first morbid event. At 12 months, the GDF-15 levels had increased by a similar amount in the placebo and valsartan groups ( P =0.94). Increases in GDF-15 over 12 months were independently associated with the risks of future mortality and first morbid event also after adjustment for clinical prognostic variables, B-type natriuretic peptide, high-sensitivity C-reactive protein, and high-sensitivity troponin T and their changes. Conclusions— GDF-15 reflects information from several pathological pathways and provides independent prognostic information in heart failure. GDF-15 levels increase over time, suggesting that GDF-15 reflects a pathophysiological axis that is not completely addressed by the therapies prescribed in Val-HeFT.

Background: Increased blood pressure (BP) response during exercise has been associated with an increased cardiovascular risk. It is unknown how LDL-cholesterol (LDL-c) is related to the exercise-induced BP response as well as to the large (LAE) and small artery (SAE) elasticity in subjects free from overt cardiovascular disease (CVD). We examined the relationship between serum LDL-c and the BP response during a moderate exercise treadmill test in subjects with no overt CVD and also the relationship between LDL-c and LAE and SAE. Methods: 1229 Subjects (700 male, 529 female) free of overt CVD were recruited during a CVD prevention screening program. A fasting venous blood sample was taken for LDL-cholesterol determination. LAE and SAE were derived from radial pulse wave contour analysis. Resting BP was measured. Then they performed a treadmill exercise test for 3 minutes at a 5 METS (metabolic equivalents) workload. Systolic and diastolic BP were measured at the peak of the 3 min exercise test, The study population was divided in quartiles among distribution of LDL-cholesterol (LDL-c). Results: Table 1 summarizes the results. There was no significant difference in large artery elasticity. Conclusions: In asymptomatic subjects, LDL-c is not related with resting BP. Higher LDL-c is related with higher exercise systolic BP response. This higher BP response can be explained by a lower smaller artery elasticity which is a marker for endothelial dysfunction probably related to higher LDL-c. Further studies to examine the effect of lipid-lowering therapy on exercise BP response are warranted Table 1

Background: Growth-Differentiation Factor-15 (GDF-15) is a member of the TGF-β family that is induced in the heart after myocardial injury. In patients with non-ST segment elevation ACS, GDF-15 is increased and provides prognostic information. Its role in heart failure is unknown. Methods & Results: GDF-15 was measured in 1125 Val-HeFT patients at baseline. Baseline median GDF-15 was 2027 ng/L (IQ range 1447 to 2942) and was abnormal (>1200 ng/L) in 86% of patients. Patients with GDF-15 above the median had higher NYHA class, greater volume load, lower LVEF and eGFR, higher hsCRP, norepinephrine, BNP and aldosterone, lower use of beta-blockers and higher use of diuretics (all p shows survival curves for the four subgroups. In a multivariate COX analysis when both GDF-15 and BNP were above the median, the risk of death was nearly three times as great (HR 2.75, 95% CI 1.75–4.30, p Conclusion: GDF-15 is an important prognostic marker in HF, independent of other markers and adds prognostic information to that provided by BNP alone.

Background— Circulating cardiac troponin T, a marker of cardiomyocyte injury, predicts adverse outcome in patients with heart failure (HF) but is detectable in only a small fraction of those with chronic stable HF. We assessed the prognostic value of circulating cardiac troponin T in patients with stable chronic HF with a traditional (cTnT) and a new precommercial highly sensitive assay (hsTnT). Methods and Results— Plasma troponin T was measured in 4053 patients with chronic HF enrolled in the Valsartan Heart Failure Trial (Val-HeFT). Troponin T was detectable in 10.4% of the population with the cTnT assay (detection limit ≤0.01 ng/mL) compared with 92.0% with the new hsTnT assay (≤0.001 ng/mL). Patients with cTnT elevation or with hsTnT above the median (0.012 ng/mL) had more severe HF and worse outcome. In Cox proportional hazards models adjusting for clinical risk factors, cTnT was associated with death (780 events; hazard ratio=2.08; 95% confidence interval, 1.72 to 2.52; P P P P Conclusions— In this large population of patients with HF, detectable cTnT predicts adverse outcomes in chronic HF. By the highly sensitive assay, troponin T retains a prognostic value at previously undetectable concentrations.

Background— Anemia is known to be a prognostic marker for patients with heart failure. However, little is known about the prognostic value of changes in hemoglobin (Hgb) over time or about the causes of anemia. Methods and Results— Retrospective analysis of Valsartan Heart Failure Trial data indicated that the quartile of patients with the biggest average decrease in Hgb over 12 months (from 14.2 to 12.6 g/dL) had significantly ( P ≤0.01) increased risk of subsequent hospitalization (hazard ratio [HR], 1.47), morbid events (HR, 1.41), and death (HR, 1.6) compared with the quartile that exhibited little change in Hgb over 12 months (from 13.7 to 13.8 g/dL). Increasing Hgb was significantly associated with lower mortality in patients with (HR, 0.78) and without (HR, 0.79) anemia at baseline. Anemia at baseline and the changes in Hgb were independently associated with serum albumin, blood pressure, glomerular filtration rate, B-type natriuretic peptide, and C-reactive protein. Lack of anemia at baseline and increases in Hgb over 12 months were not associated with smaller left ventricular diameters or higher ejection fractions. Conclusions— Changes in Hgb over 12 months were inversely associated with subsequent risk of mortality and morbidity, independently of the effects of baseline anemia and other important predictors. Several factors were independently related to anemia at baseline and changes in Hgb, suggesting multiple causes of anemia in patients with heart failure. These findings raise important questions about the optimal level of Hgb in patients with moderate to severe heart failure and how to achieve them.

A role for locally released and circulating peptides in the progressive syndrome of heart failure has been widely entertained because of the evidence for activation of a number of these hormonal systems in experimental and clinical studies and because a satisfactory explanation for the progressive cardiac and vascular functional abnormalities in heart failure has remained elusive. Endothelin (ET) is a particularly attractive candidate because it is released by the endothelium, which is thought to be functionally abnormal in heart failure,1 2 3 and because it is a potent vasoconstrictor and growth promoter.4 5 Since vasoconstriction and myocardial and vascular growth and remodeling may characterize the syndrome,6 7 8 excess endothelin release could serve an important role in the initiation or perpetuation of these processes. Shimoyama and his associates9 report in this issue of Circulation that the nonspecific endothelin receptor (ETA and ETB) antagonist bosentan exerted a vasodilator effect in their canine model of chronic left ventricular dilation that resulted from repeated coronary embolization. Because this vasodilator effect was not demonstrable in normal dogs, the authors appropriately suggest that the endothelin system appears to be upregulated in their canine model. The very modest increases in circulating levels of ET-1 they report in this model may not be pertinent because the peptide may act largely as a local hormone. Indeed, the striking rise in circulating ET-1 levels after receptor blockade confirms the active synthetic pathway. They speculate from these data that endothelin blockade may be a useful form of therapy for heart failure. Such observations have already been extended to patients with heart failure. Kiowski et al10 recently reported that bosentan produced a dose-dependent lowering of arterial pressure, pulmonary arterial pressure, pulmonary capillary wedge pressure, and right atrial pressure in 24 subjects with dilated hearts …

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The endothelium constitutes the largest organ system in the body. “Endothelial function” refers to a multitude of physiological functions of the vascular endothelium that are achieved via secretion of diverse bioactive substances. This renders the endothelium an active participant in healthy homeostasis of the vascular wall that includes normal vasomotion, inhibition of platelet aggregation and thrombus generation, and maintenance of relative impermeability. Cardiovascular risk factors activate a number of pro-oxidative genes in the vascular wall resulting in generation of reactive oxygen species that ultimately promote endothelial release of transcriptional and growth factors, proinflammatory cytokines, chemoattractant substances, and adhesion molecules.1–3 This complex cascade of events underlies the transition from normal endothelial function to endothelial dysfunction. One of the earliest manifestations of increased vascular oxidant stress is the reduced bioavailability of nitric oxide (NO) as a result of inhibition and uncoupling of endothelial NO synthase, the enzyme responsible for generation of NO, and from rapid catabolism of available NO by reactive oxygen species to peroxynitrite and hydrogen peroxide that can further amplify vascular oxidative stress. The resulting functional consequences include abnormal vasomotor activity, development of a procoagulant endothelial surface, inflammation, and, ultimately, plaque formation. Clinical measurements of endothelium-dependent vasodilation (NO-mediated process) by a variety of different techniques provide a marker of endothelial integrity. Almost all conventional risk factors for atherosclerosis are associated with endothelial dysfunction. These include sedentary lifestyle and obesity, hypercholesterolemia, hypertension, diabetes, insulin resistance, smoking, and aging. The extent of endothelial dysfunction appears to correlate with the traditional risk factor “burden,” thus implying that combined or repeated injury to the vascular endothelium results in greater dysfunction. Nevertheless, there is considerable heterogeneity in the magnitude of dysfunction observed in individuals with similar risk factor profiles.4,5 Novel risk factors such as infections, hyperhomocystinemia, genetic heterogeneity, and the variable duration of …

The clinical complications of atherosclerosis and atherothrombotic disease represent the major causes of morbidity and mortality in the United States and worldwide. The disorders that shorten life expectancy include myocardial infarction and ischemia, heart failure, stroke, renal failure, peripheral vascular disease, sudden death, and dementia, in all of which atherothrombotic disease is the most common cause. Efforts to delay or prevent these morbid events have been the focus of all clinical trials aimed at documenting the efficacy of therapeutic interventions. Furthermore, these events have served as the definition of disease used to establish population risk and risk factors. The underlying disease that eventuates in these morbid events begins in the arterial wall and progresses through well-known mechanisms that include endothelial dysfunction, inflammation, plaque formation, plaque rupture, and thrombosis. Risk factors are markers that are statistically related to the risk of morbid events, presumably because they identify or contribute to one or more of the vascular processes that lead to these events, but they do not necessarily identify the disease itself. New insights and expanding technology now make it possible to identify …

Background— Brain natriuretic peptide (BNP) and norepinephrine (NE) are strongly related to severity of and are independent predictors of outcome in heart failure. The long-term effects of angiotensin receptor blockers on BNP and NE in heart failure patients are not known. Methods and Results— Both BNP and NE were measured in 4284 patients randomized to valsartan or placebo in the Valsartan Heart Failure Trial (Val-HeFT) at baseline and 4, 12, and 24 months after randomization. The effects of valsartan were tested by ANCOVA, controlling for baseline values and concomitant ACE inhibitors and/or β-blockers. BNP and NE concentrations were similar at baseline in the 2 groups and were decreased by valsartan starting at 4 months and up to 24 months. BNP increased over time in the placebo group. At the end point, least-squares mean (±SEM) BNP increased from baseline by 23±5 pg/mL in the placebo group (n=1979) but decreased by 21±5 pg/mL (n=1940) in the valsartan group ( P P =0.0003). Concomitant therapy with both ACE inhibitors and β-blockers significantly reduced the effect of valsartan on BNP but not on NE ( P for interaction=0.0223 and 0.2289, respectively). Conclusions— In Val-HeFT, the largest neurohormone study in patients with symptomatic chronic heart failure, BNP and NE rose over time in the placebo group. Valsartan caused sustained reduction in BNP and attenuated the increase in NE over the course of the study. These neurohormone effects of valsartan are consistent with the clinical benefits reported in Val-HeFT.

Background — In chronic heart failure, sympathetic activation is increased. Moxonidine acts on central nervous system receptors to decrease sympathetic activation. We investigated the dose-response relationship of a new sustained-release (SR) preparation of moxonidine and the plasma concentration of norepinephrine in patients with chronic heart failure. Methods and Results — A total of 268 patients with chronic heart failure in NYHA functional class II to IV on optimal standard therapy were randomized to placebo or 1 of 5 doses of moxonidine SR: 0.3, 0.6, 0.9, 1.2, or 1.5 mg BID. After a dose-titration phase (7 weeks), patients were followed up for another 12 weeks at their maximally tolerated dose. Blood samples for plasma norepinephrine were collected at baseline and weekly during the initial 7 weeks, at week 19, and at the end of the study. At baseline and 7 and 19 weeks, sampling was also done 4 hours after the dose. After the active phases of the study, plasma norepinephrine was evaluated for an additional 3 days. A marked, statistically significant dose-related decrease in plasma norepinephrine was observed for predose levels as well as 4 hours after the dose at week 19. At the highest dose (1.5 mg BID), the trough reduction in norepinephrine was 52%. These reductions were accompanied by a modest decrease in heart rate, a modest increase in left ventricular ejection fraction, and a dose-related increase in adverse events. Conclusions — Plasma norepinephrine was markedly reduced in a dose-related manner by moxonidine SR. This reduction was accompanied by evidence of reverse remodeling, but also by an increase in adverse events.

Background The role of adenosine as a neuromodulator in heart failure was studied with the use of a selective adenosine A 1 receptor agonist, N 6 -cyclohexyl-2′- O -methyladenosine (SDZ-WAG 994). Methods and Results Fifty patients with heart failure symptoms and moderate left ventricular systolic dysfunction had a balloon flotation catheter inserted. Patients received placebo or a single oral dose of either 1, 2, or 5 mg SDZ-WAG 994. After baseline measurements were obtained, hemodynamic and electrophysiological recordings were repeated at 30-minute intervals for the next 4 hours, then every 6 hours for the next 24 hours. Blood samples for norepinephrine, epinephrine, aldosterone, atrial natriuretic peptide, and plasma renin activity were drawn at baseline and 2 hours after drug administration. A 1 adenosine receptor agonism produced no important effects on systemic, right atrial, pulmonary artery, or pulmonary capillary wedge pressures; cardiac index; respiratory rate; or heart rate. The PR interval (a reflection of A 1 receptor–mediated activity) increased significantly in a stepwise fashion. At the 5-mg dose of SDZ-WAG 994, significant increases in atrial natriuretic peptide (216±137 to 407±146 pg/mL) and norepinephrine (477±243 to 618±237 pg/mL) levels were noted. Conclusions A 1 adenosine receptor agonism with SDZ-WAG 994 resulted in no significant hemodynamic changes at rest in this subset of patients with left ventricular dysfunction. An increase in the PR interval and atrial natriuretic peptide level, consistent with adenosine A 1 receptor–mediated activity, was observed. In addition, an increase in the norepinephrine level was observed, suggesting a role for adenosine as a peripheral nervous system neuromodulator.

BACKGROUND Progressive ventricular remodeling after myocardial damage is associated with a poor prognosis. Optimal prevention of the histopathological processes involved in remodeling requires a more complete understanding of the mechanisms involved in initiating and maintaining these structural changes. Since the sympathetic nervous system and the renin-angiotensin system may be involved in the remodeling process, the structural effects of pharmacological inhibitors have been evaluated in a canine model of localized myocardial injury resulting from transmyocardial DC shock. METHODS AND RESULTS The study is comprised of two protocols run in series. In protocol 1, zofenopril (Z), a converting enzyme inhibitor (CEI), prevented the increase in left ventricular mass (LVM) and end-diastolic volume (LVV) observed in the control group (C) at 16 weeks (Z: LVM, 69.8 +/- 3.4 to 65.4 +/- 2.6 g, P = NS; LVV, 45.4 +/- 2.7 to 51.6 +/- 2.7 mL, P = NS; C: LVM, 68.4 +/- 3.2 to 91.4 +/- 2.9 g, P = .0001; LVV, 56.6 +/- 3.0 to 71.9 +/- 2.4 mL, P = .0003). Terazosin, an alpha 1-adrenoceptor antagonist, failed to prevent remodeling at 16 weeks despite continued receptor blockade. In protocol 2, the antiremodeling effect of full-dose CEI therapy with ramipril was confirmed. Low-dose ramipril that exerted no hemodynamic effect failed to prevent remodeling (LVM, 89.7 +/- 4.6 to 105.7 +/- 3.4 g, P = .01; LVV, 61.8 +/- 3.8 to 76.8 +/- 3.3 mL, P = .002). An angiotensin II subtype 1 receptor blocker also failed to prevent the increase in LVM or LVV (LVM, 89.0 +/- 4.6 to 109.7 +/- 5.3 g, P = .0001; LVV, 66.0 +/- 1.9 to 78.4 +/- 3.6 mL, P = .007). CONCLUSIONS High-dose CEI therapy can prevent progressive structural changes resulting from localized myocardial damage induced by DC shock. the failure of alpha 1-adrenoceptor blockade and angiotensin II subtype 1 blockade to attenuate remodeling argues against an important direct role for norepinephrine acting through alpha 1-receptors or angiotensin II acting through the type 1 receptor in the remodeling process in this model.

For those who have comfortably accepted the mechanistic link between sympathetic nervous system activation and poor outcome in heart failure, the study by Brede et al1 in this issue of Circulation is a welcome confirmation. The authors appear to have demonstrated in a murine model that absence of sympathoinhibitory α2 adrenoreceptors is associated with overactive catecholamine release, aggressive remodeling of the left ventricle, worsening signs of heart failure, and shortened life expectancy. Provocatively, deletion polymorphism of the α2 receptor in patients with heart failure also appears to be associated with worse heart failure and poorer outcome. See p 2491 One may, of course, quibble with some experimental shortcomings. The number of animals is small, and surgical mortality is neither addressed nor accounted for. The magnitude of circulating norepinephrine increase in the at-risk receptor-deficient mice is surprisingly modest. The clinical material has been assessed retrospectively from a database that is poorly described and not available for scrutiny. Furthermore, the experimental model of pressure overload from aortic banding bears little similarity to the syndrome of heart failure observed clinically. Nonetheless, the apparent …

BACKGROUND The outcomes of patients treated with implantable defibrillators were compared between patients with left ventricular ejection fraction greater than or equal to 30% and less than 30%. METHODS AND RESULTS Of 68 consecutive patients treated with implantable defibrillators, 40 patients (group 1) had left ventricular ejection fraction greater than or equal to 30%, and 28 patients (group 2) had left ventricular ejection fraction less than 30%. Sudden death, surgical mortality, nonsudden arrhythmia-related death (death within 24 hours after an arrhythmic event despite initial termination of the arrhythmia by the implantable defibrillator), total arrhythmia-related death (including sudden death, surgical death, and nonsudden arrhythmia-related death), and total cardiac death were compared between the two groups. Surgical mortality was 4.4% (0% in group 1, 11% in group 2). During the follow-up of 31 +/- 27 months, actuarial survival rates free of events were 97%, 97%, and 97% in group 1 and 96%, 91%, and 82% in group 2 at 12, 24, and 36 months, respectively, for sudden death (p = NS); 97%, 97%, and 97% in group 1 and 85%, 81%, and 72% in group 2 at 12, 24, and 36 months, respectively, for sudden death and surgical mortality (p less than 0.05); 97%, 97%, and 97% in group 1 and 82%, 78%, and 70% in group 2 at 12, 24, and 36 months, respectively, for total arrhythmia-related death (p less than 0.05); and 95%, 95%, and 95% in group 1 and 82%, 69%, and 57% in group 2 at 12, 24, and 36 months, respectively, for total cardiac death (p less than 0.05). Four (57%) of seven nonsudden cardiac deaths during the initial 36-month follow-up period were causally related to arrhythmia (three surgical deaths and one arrhythmia-related nonsudden death). CONCLUSIONS The outcome of patients treated with implantable defibrillators is strongly influenced by the degree of left ventricular dysfunction. In group 1 patients, surgical mortality, sudden death, and total cardiac death are rare. In group 2, sudden death rate may not be markedly different from that of group 1 patients. However, the risk of therapy (surgical mortality) is high. Many nonsudden cardiac deaths are causally related to arrhythmia (surgical mortality or nonsudden arrhythmia-related death). Therefore, the survival rate free of total arrhythmia-related death is significantly lower in group 2 (70% versus 97% in group 1 at 3 years). Further studies are needed to determine the roles of defibrillator therapy and other therapies in various clinical settings.

The early trials of efficacy of therapy for heart failure focused on exercise tolerance as a guide to symptom relief. Patients with heart failure usually seek medical help because of an impairment of their exercise capacity, and it seemed reasonable to use quantitative assessment of this capacity to guide our therapeutic efforts. Indeed, early studies of nitrates1 and of captopril2 3 suggested a significant improvement in peak exercise capacity when these drugs were added to conventional therapy. The duration of these studies, which were designed to demonstrate short-term improvement, was usually 3 to 6 months. Then why has exercise tolerance fallen out of favor in the continuing effort to document efficacy of therapy? A number of reasons can be cited. Peak exercise time during a progressively loaded test has a very subjective end point dependent on the motivation of both the patient and the examiner. The end point can be made more quantitative by the collection of expired gas to calculate peak oxygen consumption and to document that the subject surpassed the anaerobic threshold,4 but this adds considerable complexity to a multicenter study. Furthermore, demonstration of a statistically significant increase in exercise time does not …