Experimentally Induced Peripheral Venous Congestion Exacerbates Inflammation, Oxidative Stress, and Neurohormonal and Endothelial Cell Activation in Patients With Systolic Heart Failure.

BACKGROUND: Venous congestion (VC) is a hallmark of symptomatic heart failure (HF) requiring hospitalization; however, its role in the pathogenesis of HF progression remains unclear. We investigated whether peripheral VC exacerbates inflammation, oxidative stress and neurohormonal and endothelial cell (EC) activation in patients with HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Two matched groups of patients with HFrEF and with no peripheral VC vs without recent HF hospitalization were studied. We modeled peripheral VC by inflating a cuff around the dominant arm, targeting ∼ 30 mmHg increase in venous pressure (venous stress test [VST]). Blood and ECs were sampled before and after 90 minutes of VST. We studied 44 patients (age 53 ± 12 years, 32% female). Circulating endothelin-1, tumor necrosis factor-α, interleukin-6, isoprostane, angiotensin II (ang-2), angiopoietin-2, vascular cell adhesion molecule-1, and CD146 significantly increased after the VST. Enhanced endothelin-1 and angiopoietin-2 responses to the VST were present in patients with vs without recent hospitalization and were prospectively associated with incident HF-related events; 6698 messenger ribonucleic acid (mRNA probe sets were differentially expressed in ECs after VST. CONCLUSIONS: Experimental VC exacerbates inflammation, oxidative stress, neurohormonal and EC activation and promotes unfavorable transcriptome remodeling in ECs of patients with HFrEF. A distinct biological sensitivity to VC appears to be associated with high risk for HF progression.

Elamipretide for Barth syndrome cardiomyopathy: gradual rebuilding of a failed power grid.

Barth syndrome is a rare and potentially fatal X-linked disease characterized by cardiomyopathy, skeletal muscle weakness, growth delays, and cyclic neutropenia. Patients with Barth syndrome are prone to high risk of mortality in infancy and the development of cardiomyopathy with severe weakening of the immune system. Elamipretide is a water-soluble, aromatic-cationic, mitochondria-targeting tetrapeptide that readily penetrates and transiently localizes to the inner mitochondrial membrane. Therapy with elamipretide facilitates cell health by improving energy production and inhibiting excessive formation of reactive oxygen species, thus alleviating oxidative stress. Elamipretide crosses the outer membrane of the mitochondrion and becomes associated with cardiolipin, a constituent phospholipid of the inner membrane. Elamipretide improves mitochondrial bioenergetics and morphology rapidly in induced pluripotent stem cells from patients with Barth syndrome and other genetically related diseases characterized by pediatric cardiomyopathy. Data with elamipretide across multiple models of disease are especially promising, with results from several studies supporting the use of elamipretide as potential therapy for patients with Barth syndrome, particularly where there is a confirmed diagnosis of cardiomyopathy. This review highlights the challenges and opportunities presented in treating Barth syndrome cardiomyopathy patients with elamipretide and addresses evidence supporting the durability of effect of elamipretide as a therapeutic agent for Barth syndrome, especially its likely durable effects on progression of cardiomyopathy following the cessation of drug treatment and the capability of elamipretide to structurally reverse remodel the failing left ventricle at the global, cellular, and molecular level in a gradual manner through specific targeting of the mitochondrial inner membrane.

Paradigm shift in heart failure treatment: are cardiologists ready to use gliflozins?

Despite recent advances in chronic heart failure (HF) therapy, the prognosis of HF patients remains poor, with high rates of HF rehospitalizations and death in the early months after discharge. This emphasizes the need for incorporating novel HF drugs, beyond the current approach (that of modulating the neurohumoral response). Recently, new antidiabetic oral medications (sodium-glucose cotransporter 2 inhibitors (SGLT2i)) have been shown to improve prognosis in diabetic patients with previous cardiovascular (CV) events or high CV risk profile. Data from DAPA-HF study showed that dapaglifozin is associated with a significant reduction in mortality and HF hospitalization as compared with placebo regardless of diabetes status. Recently, results from EMPEROR-Reduced HF trial were consistent with DAPA-HF trial findings, showing significant beneficial effect associated with empagliflozin use in a high-risk HF population with markedly reduced ejection fraction. Results from the HF with preserved ejection fraction trials using these same agents are eagerly awaited. This review summarizes the evidence for the use of gliflozins in HF treatment.

Intravenous Infusion of the ß3-Adrenergic Receptor Antagonist APD418 Improves Left Ventricular Systolic Function in Dogs With Systolic Heart Failure.

BACKGROUND: Unlike ß1- and ß2-adrenergic receptors (ARs), ß3-AR stimulation inhibits cardiac contractility and relaxation. In the failing left ventricular (LV) myocardium, ß3-ARs are upregulated, and can be maladaptive in the setting of decompensation by contributing to LV dysfunction. This study examined the effects of intravenous infusions of the ß3-AR antagonist APD418 on cardiovascular function and safety in dogs with systolic heart failure (HF). METHODS AND RESULTS: Three separate studies were performed in 21 dogs with coronary microembolization-induced HF (LV ejection fraction [LVEF] of approximately 35%). Studies 1 and 2 (n = 7 dogs each) were APD418 dose escalation studies (dosing range, 0.35-15.00 mg/kg/h) designed to identify an effective dose of APD418 to be used in study 3. Study 3, the sustained efficacy study, (n = 7 dogs) was a 6-hour constant intravenous infusion of APD418 at a dose of 4.224 mg/kg (0.70 mg/kg/h) measuring key hemodynamic endpoints (e.g., EF, cardiac output, the time velocity integral of the mitral inflow velocity waveform representing early filling to time-velocity integral representing left atrial contraction [Ei/Ai]). Studies 1 and 2 showed a dose-dependent increase of LVEF and Ei/Ai, the latter being an index of LV diastolic function. In study 3, infusion of APD418 over 6 hours increased LVEF from 31 ± 1% to 38 ± 1% (P < .05) and increased Ei/Ai from 3.4 ± 0.4 to 4.9 ± 0.5 (P < .05). Vehicle had no effect on the LVEF or Ei/Ai. In study 3, APD418 had no significant effects on the HR or the systemic blood pressure. CONCLUSIONS: Intravenous infusions of APD418 in dogs with systolic HF elicit significant positive inotropic and lusitropic effects. These findings support the development of APD418 for the in-hospital treatment of patients with an acute exacerbation of chronic HF.

Barth syndrome cardiomyopathy: targeting the mitochondria with elamipretide.

Barth syndrome (BTHS) is a rare, X-linked recessive, infantile-onset debilitating disorder characterized by early-onset cardiomyopathy, skeletal muscle myopathy, growth delay, and neutropenia, with a worldwide incidence of 1/300,000-400,000 live births. The high mortality rate throughout infancy in BTHS patients is related primarily to progressive cardiomyopathy and a weakened immune system. BTHS is caused by defects in the TAZ gene that encodes tafazzin, a transacylase responsible for the remodeling and maturation of the mitochondrial phospholipid cardiolipin (CL), which is critical to normal mitochondrial structure and function (i.e., ATP generation). A deficiency in tafazzin results in up to a 95% reduction in levels of structurally mature CL. Because the heart is the most metabolically active organ in the body, with the highest mitochondrial content of any tissue, mitochondrial dysfunction plays a key role in the development of heart failure in patients with BTHS. Changes in mitochondrial oxidative phosphorylation reduce the ability of mitochondria to meet the ATP demands of the human heart as well as skeletal muscle, namely ATP synthesis does not match the rate of ATP consumption. The presence of several cardiomyopathic phenotypes have been described in BTHS, including dilated cardiomyopathy, left ventricular noncompaction, either alone or in conjunction with other cardiomyopathic phenotypes, endocardial fibroelastosis, hypertrophic cardiomyopathy, and an apical form of hypertrophic cardiomyopathy, among others, all of which can be directly attributed to the lack of CL synthesis, remodeling, and maturation with subsequent mitochondrial dysfunction. Several mechanisms by which these cardiomyopathic phenotypes exist have been proposed, thereby identifying potential targets for treatment. Dysfunction of the sarcoplasmic reticulum Ca2+-ATPase pump and inflammation potentially triggered by circulating mitochondrial components have been identified. Currently, treatment modalities are aimed at addressing symptomatology of HF in BTHS, but do not address the underlying pathology. One novel therapeutic approach includes elamipretide, which crosses the mitochondrial outer membrane to localize to the inner membrane where it associates with cardiolipin to enhance ATP synthesis in several organs, including the heart. Encouraging clinical results of the use of elamipretide in treating patients with BTHS support the potential use of this drug for management of this rare disease.

Effects of Angiotensin-Neprilysin Inhibition in Canines with Experimentally Induced Cardiorenal Syndrome.

BACKGROUND: Sacubitril/valsartan (Sac/Val), a combined angiotensin-II receptor blocker (Val) and neprilysin inhibitor (Sac) in a 1:1 molar ratio, was shown to decrease the risk of cardiovascular death or heart failure (HF) hospitalization in patients with HF and reduced left ventricular (LV) ejection fraction. This study examined the effects of Sac/Val on LV structure, function, and bioenergetics, and on biomarkers of kidney injury and kidney function in dogs with experimental cardiorenal syndrome. METHODS AND RESULTS: Fourteen dogs with cardiorenal syndrome (coronary microembolization-induced HF and renal dysfunction) were randomized to 3 months Sac/Val therapy (100 mg once daily, n = 7) or no therapy (control, n = 7). LV ejection fraction and troponin-I, as well as biomarkers of kidney injury/function including serum creatinine and urinary kidney injury molecule-1 were measured before and at end of therapy and the change (treatment effect change) calculated. Mitochondrial function measures, including the maximum rate of adenosine triphosphate synthesis, were measured in isolated cardiomyocytes at end of therapy. In Sac/Val dogs, the change in ejection fraction increased compared with controls, 6.9 ± 1.4 vs 0.7 ± 0.6%, P < .002, whereas change in troponin I decreased, -0.16 ± 0.03 vs -0.03 ± 0.02 ng/mL, P < .001. Urinary change in kidney injury molecule 1 decreased in Sac/Val-treated dogs compared with controls, -17.2 ± 7.9 vs 7.7 ± 3.0 mg/mL, P < .007, whereas the change in serum creatinine was not significantly different. Treatment with Sac/Val increased adenosine triphosphate synthesis compared with controls, 3240 ± 121 vs 986 ± 84 RLU/µg protein, P < .05. CONCLUSIONS: In dogs with cardiorenal syndrome, Sac/Val improves LV systolic function, improves mitochondrial function and decreases biomarkers of heart and kidney injury. The results offer mechanistic insights into the benefits of Sac/Val in HF with compromised renal function.

Risk Prediction in Transition: MAGGIC Score Performance at Discharge and Incremental Utility of Natriuretic Peptides.

BACKGROUND: Risk stratification for hospitalized patients with heart failure (HF) remains a critical need. The Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score is a robust model derived from patients with ambulatory HF. Its validity at the time of discharge and the incremental value of natriuretic peptides (NPs) in this setting is unclear. METHODS: This was a single-center study examining a total of 4138 patients with HF from 2 groups; hospital discharge patients from administrative data (n = 2503, 60.5%) and a prospective registry of patients with ambulatory HF (n = 1635, 39.5%). The ambulatory registry patients underwent N-terminal pro-B-type NP (BNP) measurement at enrollment, and in the hospitalize discharge cohort clinical BNP levels were abstracted. The primary endpoint was all-cause mortality within 1 year. MAGGIC score performance was compared between cohorts utilizing Cox regression and calibration plots. The incremental value of NPs was assessed using calculated area under the curve and net reclassification improvement (NRI). RESULTS: The hospitalized and ambulatory cohorts differed with respect to primary outcome (777 and 100 deaths, respectively), sex (52.1% vs 41.7% female) and race (35% vs 49.5% African American). The MAGGIC score showed poor discrimination of mortality risk in the hospital discharge (C statistic: 0.668, hazard ratio [HR]: 1.1 per point, 95% confidence interval [CI]: 0.652, 0.684) but fair discrimination in the ambulatory cohorts (C statistic: 0.784, HR: 1.16 per point, 95% CI: 0.74, 0.83), respectively, a difference that was statistically significant (P = .001 for C statistic, 0.002 for HR). Calibration assessment indicated that the slope and intercept (of MAGGIC-predicted to observed mortality) did not statistically differ from ideal in either cohort and did not differ between the cohorts (all P > .1). NP levels did not significantly improve prediction in the hospitalized cohort (P = .127) but did in the ambulatory cohort (C statistic: 0.784 [95% CI: 0.74, 0.83] vs 0.82 [95% CI: 0.78, 0.85]; P = .018) with a favorable NRI of 0.354 (95% CI: 0.202-0.469; P = .002). CONCLUSION: The MAGGIC score showed poor discrimination when used in patients with HF at hospital discharge, which was inferior to its performance in patients with ambulatory HF. Discrimination within the hospital discharge group was not improved by including hospital NP levels.

Effects of Elamipretide on Left Ventricular Function in Patients With Heart Failure With Reduced Ejection Fraction: The PROGRESS-HF Phase 2 Trial.

BACKGROUND: Elamipretide, a novel mitochondrial modulating agent, improves myocardial energetics; however, it is unknown whether this mechanistic benefit translates into improved cardiac structure and function in heart failure (HF) with reduced ejection fraction (HFrEF). The objective of this study was to evaluate the effects of multiple subcutaneous doses of elamipretide on left ventricular end systolic volume (LVESV) as assessed by cardiac magnetic resonance imaging. METHODS: We randomized 71 patients with HFrEF (LVEF ≤ 40%) in a double-blind, placebo-controlled trial in a 1:1:1 ratio to receive placebo, 4 mg or 40 mg elamipretide once daily for 28 consecutive days. RESULTS: The mean age (standard deviation) of the study population was 65 ± 10 years, 24% were females, and the mean EF was 31% ± 7%. The change in LVESV from baseline to week 4 was not significantly different between elamipretide 4 mg (89.4 mL to 85 mL; difference, -4.4 mL) or 40 mg (77.9 mL to 76.6 mL; difference, -1.2 mL) compared with placebo (77.7 mL to 74.6 mL; difference, -3.8 mL) (4 mg vs placebo: difference of means, -0.3; 95% CI, -4.6 to 4.0; P = 0.90; and 40 mg vs placebo: difference of means, 2.3; 95% CI, -1.9 to 6.5; P  =  0.28). Also, no significant differences in change in LVESV and LVEF were observed between placebo and either of the elamipretide groups. Rates of any study drug-related adverse events were similar in the 3 groups. CONCLUSIONS: Elamipretide was well tolerated but did not improve LVESV at 4 weeks in patients with stable HFrEF compared with placebo.

Effects of Intravenous Infusion of Vepoloxamer on Left Ventricular Function in Dogs with Advanced Heart Failure.

PURPOSE: Vepoloxamer (VEPO), a rheologic agent, repairs damaged cell membranes, thus inhibiting unregulated Ca2+ entry into cardiomyocytes. This study examined the effects of i.v. infusion of VEPO on LV function in dogs with coronary microembolization-induced heart failure (HF) (LV ejection fraction, EF ~ 30%). METHODS: Thirty-five HF dogs were studied. Study 1: 21 of 35 dogs were randomized to 2-h infusion of VEPO at dose of 450 mg/kg (n = 7) or VEPO at 225 mg/kg (n = 7) or normal saline (control, n = 7). Hemodynamics were measured at 2 h, 24 h, 1 week, and 2 weeks after infusion. Study 2: 14 HF dogs were randomized to 2-h infusions of VEPO (450 mg/kg, n = 7) or normal saline (control, n = 7). Each dog received 2 infusions of VEPO or saline (pulsed therapy) 3 weeks apart and hemodynamics measured at 24 h, and 1, 2, and 3 weeks after each infusion. In both studies, the change between pre-infusion measures and measures at other time points (treatment effect, Δ) was calculated. RESULTS: Study 1: compared to pre-infusion, high dose VEPO increased LVEF by 11 ± 2% at 2 h, 8 ± 2% at 24 h (p < 0.05), 8 ± 2% at 1 week (p < 0.05), and 4 ± 2% at 2 weeks. LV EF also increased with low-dose VEPO but not with saline. Study 2: VEPO but not saline significantly increased LVEF by 6.0 ± 0.7% at 2 h (p < 0.05); 7.0 ± 0.7%% at 1 week (p < 0.05); 1.0 ± 0.6% at 3 weeks; 6.0 ± 1.3% at 4 weeks (p < 0.05); and 5.9 ± 1.3% at 6 weeks (p < 0.05). CONCLUSIONS: Intravenous VEPO improves LV function for at least 1 week after infusion. The benefits can be extended with pulsed VEPO therapy. The results support development of VEPO for treating patients with acute on chronic HF.

Effectiveness of beta blockers in patients with and without a history of myocardial infarction.

PURPOSE: Studies demonstrating mortality benefit of beta blockers (BB) after myocardial infarction (MI) were conducted before the era of percutaneous intervention and widespread use of statins. Recent retrospective studies show inconsistent results regarding which subgroups of coronary artery disease (CAD) patients' benefit. Most studies did not account for medication changes over time. We evaluated the association of time-varying BB exposure with death in CAD patients with or without a history of MI. METHODS: This retrospective cohort study included all patients with MI and those with coronary disease but no MI at a single health care system who also had health insurance from January 1, 1997, to June 30, 2011. Pharmacy claims data were used to estimate BB exposure over 6-month rolling windows. The primary endpoint was all-cause death. The effect of BB exposure was tested using time-updated Cox proportional hazards models. RESULTS: We identified 6220 patients with MI and 21,285 patients with CAD but no MI. Among patients who suffered MI, BB exposure was associated with a 31% relative risk reduction in all-cause death (hazard ratio [HR] 0.69, P = 0.001). Among subjects who survived 3 years after MI, BB retained a protective association (HR 0.71, P = 0.001). Among CAD-only patients, BB exposure was also associated with risk reduction (HR 0.85, P = 0.001). CONCLUSION: Among patients with CAD, BB exposure is associated with reduced risk of death. The association is strongest among those who have suffered MI. This favorable association appears durable beyond 3 years.

Abnormalities of Mitochondrial Dynamics in the Failing Heart: Normalization Following Long-Term Therapy with Elamipretide.

PURPOSE: Abnormalities of MITO dynamics occur in HF and have been implicated in disease progression. This study describes the broad range abnormalities of mitochondrial (MITO) dynamics in Heart Failure with reduced ejection fraction (HF) and evaluates the effects of long-term therapy with elamipretide (ELAM), a MITO-targeting peptide, on these abnormalities. METHODS: Studies were performed in left ventricular tissue from dogs and humans with HF, and were compared with tissue from healthy dogs and healthy donor human hearts. Dogs with HF were randomized to 3 months therapy with ELAM or vehicle. The following were evaluated in dog and human hearts: (1) regulators of MITO biogenesis, including endothelial nitric oxide synthase (eNOS), cyclic guanosine monophosphate (cGMP), and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α, a transcription factor that drives MITO biogenesis); (2) regulators of MITO fission and fusion, including fission-1, dynamin-related protein-1, mitofusion-2, dominant optic atrophy-1, and mitofilin; and (3) determinants of cardiolipin (CL) synthesis and remodeling, including CL synthase-1, tafazzin-1, and acyl-CoA:lysocardiolipin acyltransferase-1. RESULTS: The study showed decreased levels of eNOS, cGMP, and PGC-1α in HF (dog and human). Increased levels of fission-associated proteins, decreased levels of fusion-associated proteins, decreased mitofilin, and abnormalities of CL synthesis and remodeling were also observed. In all instances, these maladaptations were normalized following long-term therapy with ELAM. CONCLUSIONS: Critical abnormalities of MITO dynamics occur in HF and are normalized following long-term therapy with ELAM. The findings provide support for the continued development of ELAM for the treatment of HF.

Pathophysiology of acute heart failure syndrome: a knowledge gap.

Although much remains unknown regarding the pathophysiology of acute heart failure (AHF), precipitating events are thought to involve a complex set of interactions between the heart, kidneys, and peripheral vasculature. In addition to these interactions, which are considered the primary abnormalities in patients with AHF, several other organ systems may also be affected and contribute to disease progression. Currently available scientific literature suggests that the natural history and pathophysiology of AHF consists of two phases: (1) an "initiation phase" involving a series of triggering events, and (2) an "amplification phase," in which multiple mechanisms contribute to worsening HF and exacerbate end-organ damage. Biomarkers of cardiac, renal, pulmonary, and other organ function have been identified during episodes of AHF, including brain natriuretic peptide, troponin I, and troponin T; biomarkers associated with AHF have proven to be useful tools for studying the pathophysiology of the syndrome, predicting clinical outcomes, and identifying patient management strategies. Despite considerable advances in recent years, AHF continues to be a leading cause of hospitalization and death in patients with chronic HF. Moreover, AHF remains a major healthcare issue exacting a considerable cost burden. Addressing this ongoing unmet need requires prioritizing efforts to better understand the natural history and pathophysiology of AHF; only then can targeted therapies be developed to prevent rehospitalization in patients with AHF, or at least alter the trajectory of disease progression toward improved clinical outcomes.

Redefining the role of biomarkers in heart failure trials: expert consensus document.

Heart failure is a growing cardiovascular disease with significant epidemiological, clinical, and societal implications and represents a high unmet need. Strong efforts are currently underway by academic and industrial researchers to develop novel treatments for heart failure. Biomarkers play an important role in patient selection and monitoring in drug trials and in clinical management. The present review gives an overview of the role of available molecular, imaging, and device-derived digital biomarkers in heart failure drug development and highlights capabilities and limitations of biomarker use in this context.

Partial Adenosine A1 Agonist in Heart Failure.

Adenosine exerts a variety of physiological effects by binding to cell surface G-protein-coupled receptor subtypes, namely, A1, A2a, A2b, and A3. The central physiological role of adenosine is to preclude tissue injury and promote repair in response to stress. In the heart, adenosine acts as a cytoprotective modulator, linking cardiac function to metabolic demand predominantly via activation of adenosine A1 receptors (A1Rs), which leads to inhibition of adenylate cyclase activity, modulation of protein kinase C, and opening of ATP-sensitive potassium channels. Activation of myocardial adenosine A1Rs has been shown to modulate a variety of pathologies associated with ischemic cardiac injury, including arrhythmogenesis, coronary and ventricular dysfunction, apoptosis, mitochondrial dysfunction, and ventricular remodeling. Partial A1R agonists are agents that are likely to elicit favorable pharmacological responses in heart failure (HF) without giving rise to the undesirable cardiac and extra-cardiac effects observed with full A1R agonism. Preclinical data have shown that partial adenosine A1R agonists protect and improve cardiac function at doses that do not result in undesirable effects on heart rate, atrioventricular conduction, and blood pressure, suggesting that these compounds may constitute a valuable new therapy for chronic HF. Neladenoson bialanate (BAY1067197) is the first oral partial and highly selective A1R agonist that has entered clinical development for the treatment of HF. This review provides an overview of adenosine A1R-mediated signaling in the heart, summarizes the results from preclinical and clinical studies of partial A1R agonists in HF, and discusses the potential benefits of these drugs in the clinical setting.

Partial adenosine A1 receptor agonism: a potential new therapeutic strategy for heart failure.

Heart failure (HF) represents a global public health and economic problem associated with unacceptable rates of death, hospitalization, and healthcare expenditure. Despite available therapy, HF carries a prognosis comparable to many forms of cancer with a 5-year survival rate of ~50%. The current treatment paradigm for HF with reduced ejection fraction (EF) centers on blocking maladaptive neurohormonal activation and decreasing cardiac workload with therapies that concurrently lower blood pressure and heart rate. Continued development of hemodynamically active medications for stepwise addition to existing therapies carries the risk of limited tolerability and safety. Moreover, this treatment paradigm has thus far failed for HF with preserved EF. Accordingly, development of hemodynamically neutral HF therapies targeting primary cardiac pathologies must be considered. In this context, a partial adenosine A1 receptor (A1R) agonist holds promise as a potentially hemodynamically neutral therapy for HF that could simultaneous improve cardiomyocyte energetics, calcium homeostasis, cardiac structure and function, and long-term clinical outcomes when added to background therapies. In this review, we describe the physiology and pathophysiology of HF as it relates to adenosine agonism, examine the existing body of evidence and biologic rationale for modulation of adenosine A1R activity, and review the current state of drug development of a partial A1R agonist for the treatment of HF.

A prospective comparison of alginate-hydrogel with standard medical therapy to determine impact on functional capacity and clinical outcomes in patients with advanced heart failure (AUGMENT-HF trial).

AIMS: AUGMENT-HF was an international, multi-centre, prospective, randomized, controlled trial to evaluate the benefits and safety of a novel method of left ventricular (LV) modification with alginate-hydrogel. METHODS: Alginate-hydrogel is an inert permanent implant that is directly injected into LV heart muscle and serves as a prosthetic scaffold to modify the shape and size of the dilated LV. Patients with advanced chronic heart failure (HF) were randomized (1 : 1) to alginate-hydrogel (n = 40) in combination with standard medical therapy or standard medical therapy alone (Control, n = 38). The primary endpoint of AUGMENT-HF was the change in peak VO2 from baseline to 6 months. Secondary endpoints included changes in 6-min walk test (6MWT) distance and New York Heart Association (NYHA) functional class, as well as assessments of procedural safety. RESULTS: Enrolled patients were 63 ± 10 years old, 74% in NYHA functional class III, had a LV ejection fraction of 26 ± 5% and a mean peak VO2 of 12.2 ± 1.8 mL/kg/min. Thirty-five patients were successfully treated with alginate-hydrogel injections through a limited left thoracotomy approach without device-related complications; the 30-day surgical mortality was 8.6% (3 deaths). Alginate-hydrogel treatment was associated with improved peak VO2 at 6 months-treatment effect vs. CONTROL: +1.24 mL/kg/min (95% confidence interval 0.26-2.23, P = 0.014). Also 6MWT distance and NYHA functional class improved in alginate-hydrogel-treated patients vs. Control (both P < 0.001). CONCLUSION: Alginate-hydrogel in addition to standard medical therapy for patients with advanced chronic HF was more effective than standard medical therapy alone for improving exercise capacity and symptoms. The results of AUGMENT-HF provide proof of concept for a pivotal trial. TRIAL REGISTRATION NUMBER: NCT01311791.

Contribution of sodium channel neuronal isoform Nav1.1 to late sodium current in ventricular myocytes from failing hearts.

KEY POINTS: Late Na(+) current (INaL) contributes to action potential remodelling and Ca(2+)/Na(+) changes in heart failure. The molecular identity of INaL remains unclear. The contributions of different Na(+) channel isoforms, apart from the cardiac isoform, remain unknown. We discovered and characterized a substantial contribution of neuronal isoform Nav1.1 to INaL. This new component is physiologically relevant to the control of action potential shape and duration, as well as to cell Ca(2+) dynamics, especially in heart failure. ABSTRACT: Late Na(+) current (INaL) contributes to action potential (AP) duration and Ca(2+) handling in cardiac cells. Augmented INaL was implicated in delayed repolarization and impaired Ca(2+) handling in heart failure (HF). We tested if Na(+) channel (Nav) neuronal isoforms contribute to INaL and Ca(2+) cycling defects in HF in 17 dogs in which HF was achieved via sequential coronary artery embolizations. Six normal dogs served as control. Transient Na(+) current (INaT ) and INaL in left ventricular cardiomyocytes (VCMs) were recorded by patch clamp while Ca(2+) dynamics was monitored using Fluo-4. Virally delivered short interfering RNA (siRNA) ensured Nav1.1 and Nav1.5 post-transcriptional silencing. The expression of six Navs was observed in failing VCMs as follows: Nav1.5 (57.3%) > Nav1.2 (15.3%) > Nav1.1 (11.6%) > Nav2.1 (10.7%) > Nav1.3 (4.6%) > Nav1.6 (0.5%). Failing VCMs showed up-regulation of Nav1.1 expression, but reduction of Nav1.6 mRNA. A similar Nav expression pattern was found in samples from human hearts with ischaemic HF. VCMs with silenced Nav1.5 exhibited residual INaT and INaL (∼30% of control) with rightwardly shifted steady-state activation and inactivation. These currents were tetrodotoxin sensitive but resistant to MTSEA, a specific Nav1.5 blocker. The amplitude of the tetrodotoxin-sensitive INaL was 0.1709 ± 0.0299 pA pF(-1) (n = 7 cells) and the decay time constant was τ = 790 ± 76 ms (n = 5). This INaL component was lacking in VCMs with a silenced Nav1.1 gene, indicating that, among neuronal isoforms, Nav1.1 provides the largest contribution to INaL. At -10 mV this contribution is ∼60% of total INaL. Our further experimental and in silico examinations showed that this new Nav1.1 INaL component contributes to Ca(2+) accumulation in failing VCMs and modulates AP shape and duration. In conclusion, we have discovered an Nav1.1-originated INaL component in dog heart ventricular cells. This component is physiologically relevant to controlling AP shape and duration, as well as to cell Ca(2+) dynamics.

Association of antidiabetic medications targeting the glucagon-like peptide 1 pathway and heart failure events in patients with diabetes.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors (GLP-1 agents) may be protective in heart failure (HF). We set out to determine whether GLP-1 agent use is associated with HF risk in diabetics. METHODS AND RESULTS: In this retrospective cohort study of members of a large health system, we identified >19,000 adult diabetics from January 1, 2000, to July 1, 2012. GLP-1 agent users were matched 1:2 to control subjects with the use of propensity matching based on age, race, sex, coronary disease, HF, diabetes duration, and number of antidiabetic medications. The association of GLP-1 agents with time to HF hospitalization was tested with multivariable Cox regression. All-cause hospitalization and mortality were secondary end points. We identified 1,426 users of GLP-1 agents and 2,798 control subjects. Both were similar except for angiotensin-converting enzyme inhibitors/angiotensin receptor blocker use, number of antidiabetic medications, and age. There were 199 hospitalizations, of which 128 were for HF, and 114 deaths. GLP-1 agents were associated with reduced risk of HF hospitalization (adjusted hazard ratio [aHR] 0.51, 95% confidence interval [CI] 0.34-0.77; P = .002), all-cause hospitalization (aHR 0.54, 95% CI 0.38-0.74; P = .001), and death (aHR 0.31, 95% CI 0.18-0.53; P = .001). CONCLUSIONS: GLP-1 agents may reduce the risk of HF events in diabetics.

Venous congestion, endothelial and neurohormonal activation in acute decompensated heart failure: cause or effect?

Venous congestion and endothelial and neurohormonal activation are known to occur in acute decompensated heart failure (ADHF), yet the temporal role of these processes in the pathophysiology of decompensation is not fully understood. Conventional wisdom presumes congestion to be a consequence of worsening cardiovascular function; however, the biomechanically driven effects of venous congestion are biologically plausible contributors to ADHF that remain largely unexplored in vivo. Recent experimental evidence from human models suggests that fluid accumulation and venous congestion are not simply consequences of poor cardiovascular function, but rather are fundamental pro-oxidant, pro-inflammatory, and hemodynamic stimuli that contribute to acute decompensation. The latest advances in the monitoring of volume status using implantable devices allow for the detection of venous congestion before symptoms arise. This may ultimately lead to improved treatment strategies including not only diuretics, but also specific, adjuvant interventions to counteract endothelial and neurohormonal activation during early preclinical decompensation.

Peripheral venous congestion causes inflammation, neurohormonal, and endothelial cell activation.

AIMS: Volume overload and venous congestion are typically viewed as a consequence of advanced and of acute heart failure (HF) and renal failure (RF) although it is possible that hypervolaemia itself might be a critical intermediate in the pathophysiology of these diseases. This study aimed at elucidating whether peripheral venous congestion is sufficient to promote changes in inflammatory, neurohormonal, and endothelial phenotype similar to those observed in HF and RF. METHODS: To experimentally model peripheral venous congestion, we developed a new method (so-called venous stress test) and applied the methodology on 24 healthy subjects (14 men, age 35 ± 2 years). Venous arm pressure was increased to ∼30 mmHg above the baseline level by inflating a tourniquet cuff around the dominant arm (test arm). Blood and endothelial cells (ECs) were sampled from test and control arm (lacking an inflated cuff) before and after 75 min of venous congestion, using angiocatheters and endovascular wires. Magnetic beads coated with EC-specific antibodies were used for EC separation; amplified mRNA was analysed by Affymetrix HG-U133 Plus 2.0 Microarray. RESULTS: Plasma interleukin-6 (IL-6), endothelin-1 (ET-1), angiotensin II (AII), vascular cell adhesion molecule-1 (VCAM-1), and chemokine (C-X-C motif) ligand 2 (CXCL2) were significantly increased in the congested arm. A total of 3437 mRNA probe sets were differentially expressed (P < 0.05) in venous ECs before vs. after testing, including ET-1, VCAM-1, and CXCL2. CONCLUSION: Peripheral venous congestion causes release of inflammatory mediators, neurohormones, and activation of ECs. Overall, venous congestion mimicked, notable aspects of the phenotype typical of advanced and of acute HF and RF.