Burkert Pieske

Inflammation as a therapeutic target in heart failure? A scientific statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology

The increasing prevalence of heart failure poses enormous challenges for health care systems worldwide. Despite effective medical interventions that target neurohumoral activation, mortality and morbidity remain substantial. Evidence for inflammatory activation as an important pathway in disease progression in chronic heart failure has emerged in the last two decades. However, clinical trials of ‘anti‐inflammatory’ therapies (such as anti‐tumor necrosis factor‐α approaches) have to date failed to show benefit in heart failure patients. The Heart Failure Association of the European Society of Cardiology recently organized an expert workshop to address the issue of inflammation in heart failure from a basic science, translational and clinical perspective, and to assess whether specific inflammatory pathways may yet serve as novel therapeutic targets for this condition. This consensus document represents the outcome of the workshop and defines key research questions that still need to be addressed as well as considering the requirements for future clinical trials in this area.

Elevation in High-Sensitivity Troponin T in Heart Failure and Preserved Ejection Fraction and Influence of Treatment With the Angiotensin Receptor Neprilysin Inhibitor LCZ696

Background—Elevated high-sensitivity troponin is associated with increasing disease severity in patients with stable heart failure with reduced ejection fraction, but less is known about the association in heart failure with preserved ejection fraction. Methods and Results—We examined the prevalence of elevated high-sensitivity troponin T (hs-TnT) in 298 patients with heart failure with preserved ejection fraction enrolled in the Prospective comparison of angiotensin receptor neprilysin inhibitor with angiotensin receptor blocker on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) trial, in which the angiotensin receptor neprilysin inhibitor LCZ696 reduced markers of heart failure severity compared with valsartan. We assessed the association between hs-TnT and cardiac structure and function, and the effect of LCZ696, compared with valsartan, on hs-TnT over 36 weeks. Elevated hs-TnT in the myocardial injury range (>0.014 &mgr;g/L) was found in 55% of patients and was associated with older age, history of diabetes mellitus, higher N-terminal pro-brain natriuretic peptide, lower estimated glomerular filtration rate, and larger left atrial size, left ventricular volume, and mass. LCZ696 treatment reduced hs-TnT to a greater extent at 12 weeks (12% reduction; P=0.05) and at 36 weeks (14% reduction; P=0.03) compared with valsartan. Conclusions—Troponin T was elevated in a substantial number of patients enrolled in a heart failure with preserved ejection fraction clinical trial and was associated with abnormalities of cardiac structure, function, and elevated baseline N-terminal pro-brain natriuretic peptide. Decreases in hs-TnT with LCZ696 in parallel with improvement in N-terminal pro-brain natriuretic peptide and left atrial size suggest that the angiotensin receptor neprilysin inhibitor LCZ696 may reduce this measure of myocardial injury in heart failure with preserved ejection fraction. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00887588.

Plasma Biomarkers Reflecting Profibrotic Processes in Heart Failure With a Preserved Ejection Fraction Data From the Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction Study

Background— Heart failure with preserved ejection fraction is a clinical syndrome that has been associated with changes in the extracellular matrix. The purpose of this study was to determine whether profibrotic biomarkers accurately reflect the presence and severity of disease and underlying pathophysiology and modify response to therapy in patients with heart failure with preserved ejection fraction.nnMethods and Results— Four biomarkers, soluble form of ST2 (an interleukin-1 receptor family member), galectin-3, matrix metalloproteinase-2, and collagen III N-terminal propeptide were measured in the Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction (PARAMOUNT) trial at baseline, 12 and 36 weeks after randomization to valsartan or LCZ696. We examined the relationship between baseline biomarkers, demographic and echocardiographic characteristics, change in primary (change in N-terminal pro B-type natriuretic peptide) and secondary (change in left atrial volume) end points. The median (interquartile range) value for soluble form of ST2 (33 [24.6–48.1] ng/mL) and galectin 3 (17.8 [14.1–22.8] ng/mL) were higher, and for matrix metalloproteinase-2 (188 [155.5–230.6] ng/mL) lower, than in previously published referent controls; collagen III N-terminal propeptide (5.6 [4.3–6.9] ng/mL) was similar to referent control values. All 4 biomarkers correlated with severity of disease as indicated by N-terminal pro B-type natriuretic peptide, E/E′, and left atrial volume. Baseline biomarkers did not modify the response to LCZ696 for lowering N-terminal pro B-type natriuretic peptide; however, left atrial volume reduction varied by baseline level of soluble form of ST2 and galectin 3; patients with values less than the observed median (<33 ng/mL soluble form of ST2 and <17.8 ng/mL galectin 3) had reduction in left atrial volume, those above median did not. Although LCZ696 reduced N-terminal pro B-type natriuretic peptide, levels of the other 4 biomarkers were not affected over time.nnConclusions— In patients with heart failure with preserved ejection fraction, biomarkers that reflect collagen homeostasis correlated with the presence and severity of disease and underlying pathophysiology, and may modify the structural response to treatment.nnClinical Trial Registration— URL: . Unique identifier: [NCT00887588][1].nn [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00887588&atom=%2Fcirchf%2F9%2F1%2Fe002551.atomBackground—Heart failure with preserved ejection fraction is a clinical syndrome that has been associated with changes in the extracellular matrix. The purpose of this study was to determine whether profibrotic biomarkers accurately reflect the presence and severity of disease and underlying pathophysiology and modify response to therapy in patients with heart failure with preserved ejection fraction. Methods and Results—Four biomarkers, soluble form of ST2 (an interleukin-1 receptor family member), galectin-3, matrix metalloproteinase-2, and collagen III N-terminal propeptide were measured in the Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction (PARAMOUNT) trial at baseline, 12 and 36 weeks after randomization to valsartan or LCZ696. We examined the relationship between baseline biomarkers, demographic and echocardiographic characteristics, change in primary (change in N-terminal pro B-type natriuretic peptide) and secondary (change in left atrial volume) end points. The median (interquartile range) value for soluble form of ST2 (33 [24.6–48.1] ng/mL) and galectin 3 (17.8 [14.1–22.8] ng/mL) were higher, and for matrix metalloproteinase-2 (188 [155.5–230.6] ng/mL) lower, than in previously published referent controls; collagen III N-terminal propeptide (5.6 [4.3–6.9] ng/mL) was similar to referent control values. All 4 biomarkers correlated with severity of disease as indicated by N-terminal pro B-type natriuretic peptide, E/E′, and left atrial volume. Baseline biomarkers did not modify the response to LCZ696 for lowering N-terminal pro B-type natriuretic peptide; however, left atrial volume reduction varied by baseline level of soluble form of ST2 and galectin 3; patients with values less than the observed median (<33 ng/mL soluble form of ST2 and <17.8 ng/mL galectin 3) had reduction in left atrial volume, those above median did not. Although LCZ696 reduced N-terminal pro B-type natriuretic peptide, levels of the other 4 biomarkers were not affected over time. Conclusions—In patients with heart failure with preserved ejection fraction, biomarkers that reflect collagen homeostasis correlated with the presence and severity of disease and underlying pathophysiology, and may modify the structural response to treatment. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00887588.

Reply: does speckle tracking really improve diagnosis and risk stratification in patients with HF with normal EF?

We appreciate the letter from Dr. Pellicori and colleagues regarding our recent paper, which described the prevalence and correlates of abnormal strain as axa0measure of left ventricular (LV) systolic function inxa0heart failure with preserved ejection fraction (HFpEF). As pointed out by Pellicori and

Relationship Between Myocardial Function and Expression of Calcium Cycling Proteins in Nonfailing and Failing Human Myocardium

Several studies, previously performed in isolated human myocardium, indicated that contractile force development is similar in failing and nonfailing myocardium at low rates of stimulation [1–4]. Accordingly, it was suggested that impaired diastolic relaxation, rather than reduced systolic force development, may be the main pathologic finding in human heart failure [4]. More recently, however, it was observed that the appearence of a contractile deficit in failing compared with nonfailing human myocardium depends on the rate of stimulation, and that contractile force development of failing myocardium is considerably reduced at higher frequencies [5–7].

Arterial hypertension drives arrhythmia progression via specific structural remodeling in a porcine model of atrial fibrillation

BACKGROUNDnArterial hypertension (HT) contributes to progression of atrial fibrillation (AF) via unknown mechanisms.nnnOBJECTIVEnWe aimed to characterize electrical and structural changes accounting for increased AF stability in a large animal model of rapid atrial pacing (RAP)-induced AF combined with desoxycorticosterone acetate (DOCA)-induced HT.nnnMETHODSnEighteen pigs were instrumented with right atrial endocardial pacemaker leads and custom-made pacemakers to induce AF by continuous RAP (600 beats/min). DOCA pellets were subcutaneously implanted in a subgroup of 9 animals (AF+HT group); the other 9 animals served as controls (AF group). Final experiments included electrophysiology studies, endocardial electroanatomic mapping, and high-density mapping with epicardial multielectrode arrays. In addition, 3-dimensional computational modeling was performed.nnnRESULTSnDOCA implantation led to secondary HT (median [interquartile range] aortic pressure 109.9 [100-137] mm Hg in AF+HT vs 82.2 [79-96] mm Hg in AF; P < .05), increased AF stability (55.6% vs 12.5% of animals with AF episodes lasting >1 hour; P < .05), concentric left ventricular hypertrophy, atrial dilatation (119 ± 31 cm2 in AF+HT vs 78 ± 23 cm2 in AF; Pxa0<xa0.05), and fibrosis. Collagen accumulation in the AF+HT group was mainly found in non-intermyocyte areas (1.62 ± 0.38 cm3 in AF+HT vs 0.96 ± 0.3 cm3 in AF; P < .05). Left and right atrial effective refractory periods, action potential durations, endo- and epicardial conduction velocities, and measures of AF complexity were comparable between the 2 groups. A 3-dimensional computational model confirmed an increase in AF stability observed in the inxa0vivo experiments associated with increased atrial size.nnnCONCLUSIONnIn this model of secondary HT, higher AF stability after 2 weeks of RAP is mainly driven by atrial dilatation.

Telbivudine in chronic lymphocytic myocarditis and human parvovirus B19 transcriptional activity: Rational and design of the PreTopic study

Myocarditis is often associated with parvovirus B19 (B19V) persistence, which can induce vascular damage. Based on the antiviral and anti‐inflammatory properties of telbivudine, we aimed to evaluate its efficacy to protect B19V‐infected endothelial cells in vitro and to treat chronic lymphocytic myocarditis patients with B19V transcriptional activity.

The CardioMEMS system in the clinical management of end-stage heart failure patients: three case reports

BackgroundRecent clinical trials have shown that pulmonary artery pressure-guided therapy via the CardioMEMS™ system reduces the risk of recurrent hospitalizations in chronic heart failure (HF) patients. The CardioMEMS™ pressure sensor is percutaneously implanted in a branch of the pulmonary artery and allows telemetric pressure monitoring via a receiver. According to the most recent ESC guidelines, this technology has currently a class IIb indication in patients with class III New York Heart Association symptoms and a previous hospitalization for congestive heart failure within the last year, regardless of ejection fraction. Aim of this guided-therapy is multifold, including an early prediction of upcoming decompensation, optimization of patients’ therapy and thereby avoidance of hospital admissions. In addition, it can be used during acute decompensation events as a novel tool to direct intra-hospital therapeutic interventions such as inotropes infusion or left ventricular (LV) assist device monitoring, with the aim of achieving an optimal volume status.Case presentationWe present a case series of three end-stage HF patients with reduced ejection fraction (HFrEF) who received a CardioMEMS™ device as an aid in their clinical management. The CardioMEMS™ system enabled a closer non-invasive hemodynamic monitoring of these patients and guided the extent of therapeutic interventions. Patients were free from device- or system-related complications. In addition, no pressure-sensor failure was observed. Two patients received a 24-h infusion of the calcium sensitizer levosimendan. One patient showed a refractory acute decompensation and underwent LV assist device (LVAD) implantation as a bridge to cardiac transplantation. Switching a patient with recurrent hospitalizations to the Angiotensin Receptor Neprilysin Inhibitor (ARNI, Sacubitril-Valsartan) on top of the optimal heart failure-therapy improved its subjective condition and hemodynamics, avoiding further hospitalization.ConclusionsOur case series underlines the potential impact of CardioMEMS™ derived data in the daily clinical management of end-stage HF patients. The new concept to combine CardioMEMS™ in the setting of an outpatient levosimendan program as well as a bridge to LVAD-implantation/heart transplantation looks promising but needs further investigations.

РЕКОМЕНДАЦИИ ESC ПО ДИАГНОСТИКЕ И ЛЕЧЕНИЮ ОСТРОЙ И ХРОНИЧЕСКОЙ СЕРДЕЧНОЙ НЕДОСТАТОЧНОСТИ 2016

2016 ESC GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF ACUTE AND CHRONIC HEART FAILURE. The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.

Altered Force-Frequency Relation and Excitation-Contraction Coupling in the Failing Human Heart: Relevance of SR-Ca2+-ATPase Protein Levels

During the last few years many experimental studies have been performed to investigate the functional alteration occurring in the failing human heart. It was shown that in isolated nonfailing human myocardium, increasing stimulation frequency results in a pronounced augmentation of myocardial performance with regard to isometric force development as well as auxotonic working capacity [1–3]. However, frequency potentiation of contractile force is blunted or even reversed in the failing human heart [1–5]. Since heart rate-dependent regulation of myocardial performance is important for the regulation of cardiovascular function, these experiminental findings may represent a major functional disturbance of the failing human heart.