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Background: The Fried Frailty Phenotype predicts adverse outcomes in geriatric populations, but has not been well-studied in advanced heart failure (HF). The Registry Evaluation of Vital Information for Ventricular Assist Devices (VADs) in Ambulatory Life (REVIVAL) study prospectively collected frailty measures in patients with advanced HF to determine relevant assessments and their impact on clinical outcomes., Methods and Results: HF-Fried Frailty was defined by 5 baseline components (1 point each): (1) weakness: hand grip strength less than 25% of body weight; (2) slowness based on time to walk 15 feet; (3) weight loss of more than 10 lbs in the past year; (4) inactivity; and (5) exhaustion, both assessed by the Kansas City Cardiomyopathy Questionnaire. A score of 0 or 1 was deemed nonfrail, 2 prefrail, and 3 or greater was considered frail. The primary composite outcome was durable mechanical circulatory support implantation, cardiac transplant or death at 1 year. Event-free survival for each group was determined by the Kaplan-Meier method and the hazard of prefrailty and frailty were compared with nonfrailty with proportional hazards modeling. Among 345 patients with all 5 frailty domains assessed, frailty was present in 17%, prefrailty in 40%, and 43% were nonfrail, with 67% (n = 232) meeting the criteria based on inactivity and 54% (n = 186) for exhaustion. Frail patients had an increased risk of the primary composite outcome (unadjusted hazard ratio [HR] 2.82, 95% confidence interval [CI] 1.52-5.24; adjusted HR 3.41, 95% CI 1.79-6.52), as did prefrail patients (unadjusted HR 1.97, 95% CI 1.14-3.41; adjusted HR 2.11, 95% CI 1.21-3.66) compared with nonfrail patients, however, the predictive value of HF-Fried Frailty criteria was modest (Harrel's C-statistic of 0.603, P = .004)., Conclusions: The HF-Fried Frailty criteria had only modest predictive power in identifying ambulatory patients with advanced HF at high risk for durable mechanical circulatory support, transplant, or death within 1 year, driven primarily by assessments of inactivity and exhaustion. Focus on these patient-reported measures may better inform clinical trajectories in this population., (Copyright © 2021. Published by Elsevier Inc.)

Background: Worsening heart failure (HF) and health-related quality of life (HRQOL) have been shown to impact the decision to proceed with left ventricular assist device (LVAD) implantation, but little is known about how socioeconomic factors influence expressed patient preference for LVAD., Methods and Results: Ambulatory patients with advanced systolic HF (n=353) reviewed written information about LVAD therapy and completed a brief survey to indicate whether they would want an LVAD to treat their current level of HF. Ordinal logistic regression analyses identified clinical and demographic predictors of LVAD preference. Higher New York Heart Association (NYHA) class, worse HRQOL measured by Kansas City Cardiomyopathy Questionnaire, lower education level, and lower income were significant univariable predictors of patients wanting an LVAD. In the multivariable model, higher NYHA class (OR [odds ratio]: 1.43, CI [confidence interval]: 1.08-1.90, P = .013) and lower income level (OR: 2.10, CI: 1.18 - 3.76, P = .012 for <$40,000 vs >$80,000) remained significantly associated with wanting an LVAD., Conclusion: Among ambulatory patients with advanced systolic HF, treatment preference for LVAD was influenced by level of income independent of HF severity. Understanding the impact of socioeconomic factors on willingness to consider LVAD therapy may help tailor counseling towards individual needs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: The aim of this work was to characterize the clinical response and identify predictors of clinical stabilization after intra-aortic balloon counterpulsation (IABP) support in patients with chronic systolic heart failure in cardiogenic shock before implantation of a left ventricular assist device (LVAD)., Background: Limited data exist regarding the clinical response to IABP in patients with chronic heart failure in cardiogenic shock., Methods: We identified 54 patients supported with IABP before LVAD implantation. Criteria for clinical decompensation after IABP insertion and before LVAD included the need for more advanced temporary support, initiation of mechanical ventilation or dialysis, increase in vasopressors/inotropes, refractory ventricular arrhythmias, or worsening acidosis. The absence of these indicated stabilization., Results: Clinical decompensation after IABP occurred in 23 patients (43%). Both patients who decompensated and those who stabilized had similar hemodynamic improvements after IABP support, but patients who decompensated required more vasopressors/inotropes. Clinical decompensation after IABP was associated with worse outcomes after LVAD implantation, including a 3-fold longer intensive care unit stay and 5-fold longer time on mechanical ventilation (P < .01 for both). Although baseline characteristics were similar between groups, right and left ventricular cardiac power indexes (cardiac power index = cardiac index × mean arterial pressure/451) identified patients who were likely to stabilize (area under the receiver operating characteristic curve = 0.82)., Conclusions: Among patients with chronic systolic heart failure who develop cardiogenic shock, more than one-half of patients stabilized with IABP support as a bridge to LVAD. Baseline measures of right and left ventricular cardiac power, reflecting work performed for a given flow and pressure, may allow clinicians to identify patients with sufficient contractile reserve who will be likely to stabilize with an IABP versus those who may need more aggressive ventricular support., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: It is unclear whether improvement in left ventricular (LV) ejection fraction (LVEF) following treatment with a combined α(1),β(1),β(2)-blockade can be attributed to improvement in LV contractility, to a reduction in afterload, and/or to improvements in LV remodeling and chamber size. We aimed to examine whether the observed improvement in LVEF following carvedilol treatment is due to changes in intrinsic myocardial contractility beyond changes in LV chamber size or loading conditions., Methods and Results: In 49 consecutive patients with chronic heart failure (HF), LVEF ≤35%, NYHA functional class II-IV, on angiotensin-converting enzyme inhibitors but not on ß-blockers, LV contractile performance and remodeling were assessed by comprehensive echocardiography at baseline and after 3 and 6 months of treatment with carvedilol. Carvedilol treatment resulted in significant improvements in LVEF, shortening fraction, and velocity of circumferential shortening (VCF(c)). There were no significant changes in the mean arterial blood pressure or systemic vascular resistance index; but LV end-systolic wall stress (LVESS), effective arterial elastance, ventriculoarterial coupling, and LV end-diastolic and end-systolic dimensions and volumes were significantly reduced. Estimated end-systolic elastance, VCF(c)-to-LVESS ratio, and pulsatile arterial compliance significantly improved after 6 months of treatment with carvedilol. The slope of the VCF(c) relationship to LVESS worsened from 0 to 3 months, but significantly improved from 3 to 6 months., Conclusions: Despite an initial transient negative inotropic effect from 0 to 3 months, carvedilol treatment was associated with a positive inotropic effect with significant improvement in load-independent indexes of myocardial contractility beyond what can be attributed to changes in LV chamber size and load after 3 months. There were no changes in systemic vascular resistance with carvedilol treatment; however, improvement in pulsatile arterial compliance and ventriculoarterial coupling suggested enhanced cardiac mechanoenergetic performance along with improved systemic arterial compliance., (Published by Elsevier Inc.)

Background: Cardiac fibrosis is a major determinant of myocardial stiffness, diastolic dysfunction, and heart failure (HF). By reducing cardiac fibrosis, aldosterone antagonists have the potential to be beneficial in heart failure with preserved ejection fraction (HFpEF)., Methods and Results: In a randomized, double-blind, placebo-controlled trial of 44 patients with HFpEF, we examined the effects of eplerenone, an aldosterone antagonist, on changes in 6-minute walk distance (primary end point), diastolic function, and biomarkers of collagen turnover (secondary end points). All patients had a history of hypertension, 61% were diabetic, and 52% had prior HF hospitalization. After 6 months of treatment, similar improvements in 6 minute walk distance were noted in the eplerenone and placebo groups (P = .91). However, compared with placebo, eplerenone was associated with a significant reduction in serum markers of collagen turnover (procollagen type I aminoterminal peptide, P = .009 and carboxy-terminal telopeptide of collagen type I, P = .026) and improvement in echocardiographic measures of diastolic function (E/E', P = .01)., Conclusions: Although eplerenone was not associated with an improvement in exercise capacity compared to placebo, it was associated with significant reduction in markers of collagen turnover and improvement in diastolic function. Whether these favorable effects will translate into morbidity and mortality benefit in HFpEF remains to be determined., (Published by Elsevier Inc.)

Guidelines have rather quickly assumed a central role in health care delivery in the U.S. They have become the foundation on which performance measures are built and, therefore, a major player in assessing the quality of care provided by individuals and institutions, the ramifications of which involve reputation, reimbursement, and litigation. We are concerned, however, that in our enthusiasm for collectively endorsing these guidelines, we are marginalizing the importance of physician judgment and inadvertently risking the conversion of guidelines into "cookbooks." We believe that this editorial, while unequivocally acknowledging the fundamental importance of guidelines, simultaneously provides a critically important perspective on the potential for misuse of both guidelines and performance measures. Further, we hope that publication of this commentary will help temper enthusiasm for overzealous conversion of guidelines into performance measures, thereby restoring the vital role of physician judgment and insight into patient management.

Background: Ventricular assist devices (VADs) are used to bridge heart failure patients to transplantation, to allow their own hearts to recover, or as permanent ("destination") therapy. To date, the use of VADs has been limited to late-stage heart failure patients because of the associated device risks. In 2008, a National Heart, Lung, and Blood Institute (NHLBI) working group met to evaluate the treatment of heart failure using VADs and to advise the institute on how therapy for heart failure may be best advanced by clinical trials involving the devices., Methods and Results: Recognizing the improvements in VAD technology and in patient care and selection over the past decade, the working group recommended that a trial be performed to assess the use of chronic VAD therapy in patients who are less ill than those currently eligible for destination therapy. The hypothesis proposed for the trial is that VAD therapy may improve both survival and quality of life in moderately advanced heart failure patients who are neither inotrope-dependent nor exercise-intolerant and have not yet developed serious consequences such as malnourishment, end-organ damage, and immobility., Conclusion: Based on the group's recommendations, NHLBI issued an RFP in 2009 for the REVIVE-IT Pilot Trail, which will serve to test the hypothesis and inform the pivotal trial., (Published by Elsevier Inc.)

Recently, the American Board of Medical Specialties approved a proposal from the American Board of Internal Medicine for establishing the secondary subspecialty of Advanced Heart Failure and Transplant Cardiology. This step represents culmination of a process that began 4 years ago, through advocacy by the Heart Failure Society of America. It represents an essential step to ensure quality of care by specialists in a field that has grown up de facto amid rapid expansion both of the population of patients with heart failure and of diagnostic and therapeutic options for their management. The vast majority of care for most patients with heart failure will continue to be provided by general internists and cardiologists. Certification in Advanced Heart Failure and Transplant Cardiology will require a high degree of competency in all aspects of heart failure care, including technical proficiencies required to manage patients undergoing heart transplant and device implants. These specialists will play a key role in delivering the highest quality of complex care in the most cost-effective manner. In the years to come, the specialty must adapt to the ongoing rapid expansion of evidence-based knowledge in this field to continue to provide the highest level of care and the best outcomes to patients with heart failure.

Background: In the general population, 27% of adults have the metabolic syndrome (MetS) and is associated with increased mortality. Similar data are not available for a heart failure (HF) population. This study sought to determine the prevalence of the MetS and its effect on mortality in a HF population., Methods and Results: Patients (n = 886) discharged from the hospital with a primary diagnosis of HF were retrospectively identified. Demographic, clinical, and laboratory data were extracted by chart review. The MetS was defined according to National Cholesterol Education Program Expert Panel criteria with a body mass index >or=30 kg/m(2) substituted for increased waist circumference. Mortality data were acquired by query of the National Death Index, with a median follow-up of 856 days. Data were available to evaluate for the presence or absence of MetS in 71% (n = 625). The prevalence of MetS in this cohort was 68%. MetS was most common in Hispanics (79%) compared with whites (70%) and blacks (61%, P = .003). Mortality was lower in those with MetS (44%) compared with those without (58%, unadjusted HR 0.67 [95% CI, 0.53-0.85]). In a fully adjusted model, there was still a significantly lower risk of mortality in those with MetS (adjusted HR 0.73 [95% CI, 0.56-0.94])., Conclusions: In a cohort hospitalized with HF, the prevalence of MetS exceeds that of the general population, and unlike the general population, MetS is associated with a lower mortality.

Background: Inflammatory pathways may promote extracellular matrix (ECM) remodeling and chronic heart failure (CHF) progression. The relationship between markers of inflammation and of ECM remodeling, and their influence on functional status and outcomes has not been examined in a large cohort of CHF patients., Methods and Results: We measured baseline blood serum collagen (amino-terminal propeptide of collagen III [PIIINP], metalloproteinase 1 [MMP-1], tissue inhibitor of metalloproteinase 1 [TIMP-1]), and inflammatory (high-sensitivity C-reactive protein [(hsCRP], interleukin [IL]-18, IL-10) markers in 1009 patients enrolled in the Research into Etanercept Cytokine Antagonism in Ventricular Dysfunction (RECOVER) trial. A positive correlation was detected between the 2 classes of markers (PIIINP to IL-18, MMP-1 and TIMP-1 to CRP, TIMP-1 to IL-18, MMP-1 to IL-10). In the adjusted multivariable model including all biomarkers, only PIIINP (P = .03) and MMP-1 (P = .048) were independent predictors of 6-minute walk test (6-MWT), whereas in another model including only inflammatory biomarkers, IL-18 was an independent predictor. PIIINP (P = .001) was the only biomarker independently associated with death and CHF hospitalization., Conclusions: The independent associations of PIIINP and MMP-1 with 6-MWT and PIIINP with CHF morbi-mortality suggest that excessive ECM turnover may be associated with functional capacity deterioration and poor outcome.

Background: There is increased interest in mechanical circulatory support devices (MCSDs), such as implantable left ventricular assist devices (LVADs), as "destination" therapy for patients with advanced heart failure. Because patient availability to evaluate these devices is limited and randomized trials have been slow in enrolling patients, a workshop was convened to consider designs for MCSD development including alternatives to randomized trials., Methods and Results: A workshop was jointly planned by the Heart Failure Society of America and the US Food and Drug Administration and was convened in March 2006. One of the panels was asked to review different designs for evaluating new MCSDs. Randomized trials have many advantages over studies with no controls or with nonrandomized concurrent or historical controls. These advantages include the elimination of bias in the assignment of treatments and the balancing, on average, of known and unknown baseline covariates that influence response. These advantages of randomization are particularly important for studies in which the treatments may not differ from one another by a large amount (eg, a head-to-head study of an approved LVAD with a new LVAD). However, researchers have found it difficult to recruit patients to randomized studies because the number of clinical sites that can carry out the studies is not large. Also, there is a reluctance to randomize patients when the control device is considered technologically inferior. Thus ways of improving the design of randomized trials were discussed, and the advantages and disadvantages of alternative designs were considered., Conclusions: The panel concluded that designs should include a randomized component. Randomized designs might be improved by allowing the control device to be chosen before randomization, by first conducting smaller vanguard studies, and by allowing crossovers in trials with optimal medical management controls. With use of data from completed trials, other databases, and registries, alternative designs that include both a randomized component (eg, 2:1 allocation for new device versus control) and a nonrandomized component (eg, concurrent nonrandomized control, historical control, or a comprehensive cohort design) should be evaluated. This will require partnerships among academic, government, and industry scientists.

Heart failure may be viewed as a progressive disorder that is impelled, at least in part, by progressive left ventricular (LV) remodeling. In the present discussion we will review the role of LV remodeling in the pathogenesis of heart failure, with a focus on the contribution that increased wall stress plays in the development and progression of LV remodeling. The clinical implication of this review is that existing neurohormonal strategies may not completely prevent disease progression in the failing heart, and that adjunctive strategies that are designed to specifically prevent or attenuate LV remodeling may play an important role in the clinical treatment of heart failure.

Background: Heart failure remains a progressive disease with incremental morbidity and mortality despite optimal medical therapy. A growing body of evidence suggests that progressive left ventricular (LV) remodeling is directly related to a deterioration in LV performance and untoward clinical outcomes for heart failure patients. Preclinical and early phase I clinical studies with the CorCap Cardiac Support Device (CSD), a passive cardiac support device that prevents cardiac remodeling, have shown that it is safe and is associated with improvements in LV structure and function, as well as patient symptomatology., Methods and Results: The Acorn Pivotal Trial is a pivotal prospective, randomized, evaluation of the CorCap CSD in patients with New York Heart Association class III-IV heart failure. Patients will be enrolled into one of two different strata. Patients who require a mitral valve repair/replacement (MVR) will fall into the "MVR stratum" and will be randomized to either treatment (MVR surgery plus the CSD) or control (MVR surgery alone). Patients who do not have a clinical indication for MVR surgery will fall into the "no-MVR stratum" and will also be randomized to either treatment (CSD implant plus optimal medical therapy) or control (optimal medical therapy alone). A total of 300 patients (150 treatment and 150 control) will be enrolled. The primary endpoint of the trial is the change in clinical status from baseline to the end of the efficacy phase (1 year), as determined by a clinical composite score. Patients will be classified as improved, worsened, or unchanged based upon patient vital status, the occurrence of a major cardiac procedure indicative of heart failure progression, and a change in the assessment of New York Heart Association functional class., Conclusions: The Acorn Pivotal Trial will formally test the hypothesis that preventing LV remodeling using a passive cardiac support device will favorably impact the untoward natural history of heart failure and thus represents an important departure from all previous medical and device studies that have been reported to date.

Objectives: The risks and benefits of beta-blockade with bucindolol were assessed in heart failure (HF) patients with Class IV symptoms within the Beta-blocker Evaluation of Survival Trial (BEST)., Background: beta-blockade is accepted therapy for mild to moderate HF, but its safety and efficacy in advanced HF have not been established., Methods: BEST recruited 2708 HF patients; of these, 226 with Class IV symptoms (n=114 randomized to bucindolol, n=112 to placebo) formed the basis of this study. All-cause death, HF hospitalization, and drug discontinuations occurring early during therapy (< or =6 months) and overall during follow-up were assessed. Compared with Class III, Class IV patients were older and had higher plasma norepinephrine levels, prevalence of coronary disease, S3 gallops, and lower ejection fractions, but characteristics of the 2 Class IV treatment groups were similar., Results: During a mean of 1.6 years, 49% Class IV patients died, and 54% were hospitalized for HF. Bucindolol increased the combined endpoint of death or HF hospitalization within the first 6 months (hazard ratio [HR]=1.7, 95% confidence interval [CI]=1.1-2.7) and did not result in benefit overall (HR=1.2, 95% CI=0.9-1.6). HF hospitalization alone within 6 months was increased by bucindolol (HR=1.7), and an early adverse trend for death was seen (HR=1.6) with no benefit overall (HR=1.1). Bucindolol was discontinued more frequently than placebo for worsening HF (11% versus 4%) and hypotension (3% versus 0%)., Conclusions: Class IV HF patients in BEST were at high risk. Bucindolol did not reduce death or HF hospitalization and was associated with early hazard.

Background: Changes in myocardial matrix metalloproteinases (MMPs) and the inhibitors of MMPs (TIMPs) have been demonstrated in congestive heart failure (CHF). The first objective of this study was to measure plasma profiles of MMPs and TIMPs in CHF patients (n = 24; 62 +/- 3 years; left ventricular ejection fraction [LVEF] = 24 +/- 2%) and age-matched nonfailing patients (n = 48; 63 +/- 2 years; LVEF >/= 55%). Cytokines such as tumor necrosis factor (TNF)-alpha can induce MMP expression in vitro. The second objective of this study was to determine the relationship between soluble TNF-alpha receptors (TNFR1; TNFR2) and MMP plasma profiles., Methods and Results: Plasma levels of MMP-2, MMP-9, MMP-8, TIMP-1, TIMP-2, TNF-alpha, TNFR1, and TNFR2 were measured by enzyme-linked immunosorbent assay kits. Plasma MMP-9 levels were increased in CHF patients (25 +/- 6 versus 72 +/- 15 ng/mL, P <.05). Interestingly, plasma levels of MMP-8 were decreased in CHF patients (16 +/- 2 versus 9 +/- 2 ng/mL, P <.05). The MMP-9/TIMP-1 ratio was increased by 3-fold, whereas the MMP-9/TIMP-2 ratio was increased by 16-fold in CHF patients (both P <.05). With a 48-week follow-up in CHF patients, an absolute reduction in plasma TNFR1 from baseline was accompanied by reduced MMP-9 levels (-30 +/- 16 ng/mL; P =.058), whereas stable or increased plasma TNFR1 resulted in persistently elevated MMP-9 levels., Conclusions: The unique findings of this study were 2-fold. First, a discordant change in plasma MMP and TIMP levels occurred in CHF patients. Second, changes in cytokine activity were related to changes in plasma MMP levels. These changes in MMP/TIMP levels likely reflect the progression and/or acceleration of the LV remodeling process in CHF. Thus serial measurements of plasma MMP/TIMP levels may hold diagnostic/prognostic significance in CHF patients.

Recent studies have identified the importance of biologically active molecules such as neurohormones in disease progression in heart failure. More recently, it has become apparent that in addition to neurohormones another portfolio of biologically active molecules termed cytokines are also expressed in the setting of heart failure. This article will review the role of tumor necrosis factor-induced signal transduction and the process of left ventricular remodeling.

Background: Inflammatory mediators, especially tumor necrosis factor (TNF), have been implicated in heart failure (HF). Thalidomide has anti-inflammatory properties and selectively inhibits TNF. Thus far, thalidomide or thalidomide analogues have not been evaluated in patients with heart failure., Methods: Thalidomide was assessed in preclinical and clinical studies. First, isolated cardiac myocytes were pretreated with thalidomide or thalidomide analogues, and TNF production was assessed after lipopolysaccharide (LPS) provocation. Second, to determine the safety and potential efficacy of thalidomide, an open-label dose escalation safety study was conducted in seven patients with advanced heart failure., Results: Thalidomide and thalidomide analogues inhibited LPS-induced TNF biosynthesis in cardiac myocytes in a dose-dependent manner. Thalidomide analogues had a greater inhibitory effect on TNF production than did thalidomide. In patients with advanced HF, thalidomide was safe and potentially effective when used at lower doses. However, dose-limiting toxicity was observed in two patients. There was a significant increase in the 6-minute walk distance and a trend toward improvement in left ventricular ejection fraction and quality of life after 12 weeks of maintenance therapy with thalidomide., Conclusions: Taken together these results suggest that thalidomide or its derivatives may be useful in selected patients with HF. This potential needs to be studied in larger clinical trials.

The ability of the myocardium to successfully compensate for and adapt to stress, ultimately determines whether the heart will decompensate and fail, or whether instead it will maintain preserved function. Despite the importance of the myocardial response to environmental stress, very little is known with respect to the biochemical mechanisms that are responsible for mediating and integrating the stress response in the heart. In the present review we will summarize recent experimental material which suggests that tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory cytokine that has been identified consistently in virtually all forms of cardiac injury, may play an important role in mediating and integrating the myocardial response to stress. The theme that will emerge from this discussion is that the short-term expression of TNF-alpha within the heart may provide the heart with an adaptive response to stress, whereas long-term expression of TNF-alpha may be frankly maladaptive by producing cardiac decompensation.

Although the development and progression of heart failure have traditionally been viewed as hemodynamic disorders, there is now an increasing awareness that the syndrome of heart failure cannot be simply and/or precisely defined solely in hemodynamic terms. The inability of the so-called hemodynamic hypothesis to explain the progression of heart failure has given rise to the notion that heart failure may progress as a result of the overexpression of an ensemble of biologically active molecules referred to generically as neurohormones. More recently, it has become apparent that in addition to neurohormones, another portfolio of biologically active molecules, termed cytokines, are also expressed in the setting of heart failure. This article reviews recent clinical and experimental material that suggests that the cytokines, much like the neurohormones, may represent another class of biologically active molecules that are responsible for the development and progression of heart failure.