Clinical and economic impact of HeartLogic (TM) compared with standard care in heart failure patients

Aims The implantable cardiac defibrillator/cardiac resynchronization therapy with defibrillator-based HeartLogic (TM) algorithm has recently been developed for early detection of impending decompensation in heart failure (HF) patients; but whether this novel algorithm can reduce HF hospitalizations has not been evaluated. We investigated if activation of the HeartLogic algorithm reduces the number of hospital admissions for decompensated HF in a 1 year post-activation period as compared with a 1 year pre-activation period.Methods and results Heart failure patients with an implantable cardiac defibrillator/cardiac resynchronization therapy with defibrillator with the ability to activate HeartLogic and willingness to have remote device monitoring were included in this multicentre non-blinded single-arm trial with historical comparison. After a HeartLogic alert, the presence of HF symptoms and signs was evaluated. If there were two or more symptoms and signs apart from the HeartLogic alert, lifestyle advices were given and/or medication was adjusted. After activation of the algorithm, patients were followed for 1 year. HF events occurring in the 1 year prior to activation and in the 1 year after activation were compared. Of the 74 eligible patients (67.2 +/- 10.3 years, 84% male), 68 patients completed the 1 year follow-up period. The total number of HF hospitalizations reduced from 27 in the pre-activation period to 7 in the post-activation period (P = 0.003). The number of patients hospitalized for HF declined from 21 to 7 (P = 0.005), and the hospitalization length of stay diminished from average 16 to 7 days (P = 0.079). Subgroup analysis showed similar results (P = 0.888) for patients receiving cardiac resynchronization therapy during the pre-activation period or not receiving cardiac resynchronization therapy, meaning that the effect of hospitalizations cannot solely be attributed to reverse remodelling. Subanalysis of a single-centre Belgian subpopulation showed important reductions in overall health economic costs (P = 0.025).Conclusion Activation of the HeartLogic algorithm enables remote monitoring of HF patients, coincides with a significant reduction in hospitalizations for decompensated HF, and results in health economic benefits.Cardiolog

Biomarkers to predict the response to cardiac resynchronization therapy

Cardiac resynchronization therapy (CRT) is an established non-pharmacological treatment for selected heart failure patients with wide QRS duration. However, there is a persistent number of non-responders throughout. The prediction of the CRT response is paramount to adequately select the correct patients for CRT. One of the expanding fields of research is the development of biomarkers that predict the response to CRT. A review of the available literature on biomarkers in CRT patients has been performed to formulate a critical appraisal of the available data. The main conclusion of our review is that biomarker research in this patient population is very fragmented and broad. This results in the use of non-uniform endpoints to define the CRT response, which precludes an in-depth comparison of the available data. To improve research development in this field, a uniform definition of the CRT response and relevant endpoints is necessary to better predict the CRT response

The role of micro-RNA -221 and -222 in the pathophysiology of viral myocarditis

Introduction and background Viral myocarditis is a major health problem: up to 40% of sudden death in young people is due to myocarditis – adverse inflammation – in the heart (1). A lot of viruses can cause myocarditis, but especially rhinoviruses and enteroviruses are responsible pathogens (2). Cardiac inflammation plays a central role in myocarditis and heart failure, mediating cardiac hypertrophy, myocyte death and fibrosis. Identification of targets that explain why one person does get adverse cardiac inflammation, whereas many others are spared, is crucial to better understand this disease and to develop new therapeutic tools (3). The discovery of micro-RNAs (miRs), a new class of small non-coding RNAs, is among the major scientific breakthroughs in recent years. They are crucial players in the regulation of gene expression by binding to messenger RNAs (mRNAs) and inhibiting their translation into protein (4). Global goals of this project MiRs have been implicated in the pathophysiology of cancer, infectious disorders, and hypertensive and ischemic heart disease (5). However, their involvement in cardiac inflammation during viral myocarditis is largely unknown. The overall objective of this project is to unravel the precise biological roleof specific inflammation-mediated miR-221 and -222 in cardiac injury and dysfunction following viral infection, and in cardiac hypertrophy and fibrosis development. Whereas recent studies (6) mainly focused on the role of cardiomyocyte- and fibroblast-derived miRs in hypertrophy, fibrosis and arrhythmias, this project will unravel the biological role – and determine their upstream regulation – of inflammation-mediated miR-221 and -222 in cardiac inflammatory disease. Preliminary data In a mouse model of human Coxsackievirus B3 (CVB3) induced myocarditis, the comparison of miR profiles at baseline using a miR microarray resulted in the identification and further validation via quantitativertPCR of miR-221 and -222 as inflammation-related miRs, beside miR-146,-155 and -223 (7). We validated miRNA-221 and -222 as relevant targets mediating cardiac inflammation in viral myocarditis. However, their pathophysiologic role in cardiac inflammation is largely unknown. Recently, we obtained clear evidence that the absence of miR-155 (part of another project) in mice resulted in a higher mortality, with increased cardiac inflammation and injury in CVB3-myocarditis. Whereas lack of miR-155 in mice did not affect cardiac development or function at baseline, it resulted in increased cardiac inflammation and mortality compared to wild type littermates in CVB3-myocarditis (8). Fifty two percent (12/23) of miR-155 knockout mice died within 8 days after CVB3-infection compared to 6 percent of wild types (1/15), with increased cardiacinflammation and injury but a similar CVB3-load in miR-155 knockout mice. Hypothesis and specific aims of this project Both miR-221 and -222 are implicated in cancer formation and T-cell function, and have been found to modulate myogenesis (9). They are both up regulated by ERK1/2, a cell signaling pathway which is crucial in cardiac hypertrophy and fibrosis. Further encouraged by the preliminary data described above, and well-knowing that raised levels of the inflammation-related miR-221 and -222 are present in both viral myocarditis and hypertensive HD, we postulate that: MiR-221 and -222 are key regulators of cardiac inflammation in viral myocarditis. Therefore we will unravel the precise biological function of miR-221 and -222 in knockout animals and by using antagomirs. We will also determine their mRNA-targets and pathways, and study their upstream regulation, explaining their possible implication in viral myocarditis. MiR-221 and -222 may be diagnostic tools and prognostic biomarkers for the severity of heart failure in viral heart disease. We aim to translate our findings to human viral myocarditis by studying miR levels in blood samples and inflammatory cardiac tissue biopsies. We will study whether miR-221 or -222 expression is raised in the blood of patients with myocarditis compared to controls, and whether quantification of miR-221 or -222 signifies a prognostic value in HF patients. Methodology 1a. What is the biological role of miR-221 and -222 in heart failure? Do they protect against exaggerated inflammation and tissue damage? The severity of cardiac inflammation, fibrosis, tissue damage and dysfunction will be measured in miR-221 or miR-222 gene-inactivated mice (currently available) and compared to wild type mice. We will also use the commercially available antagomir-approach for these miRs, allowing an efficient and time-dependent way of miR-silencing (10). To obtain miR-221 and -222 overexpression or knockdown (with miR-spounges), an adeno-associated virus (AAV-mediated) method will be used (11). The following experimental conditions will be evaluated: (a) angiotensin-II induced hypertension, 7 and 28 days; (b) human Coxsackievirus B3-induced myocarditis, 7 and 35 days; (c) myocardial infarction by persistent left coronary ligation, 7 and 14 days. Heart function will be quantified with ultrasound- and electrocardiography, and by invasive intracardial pressure measurements. After obduction, hearts will be prepared for histological and molecular investigations. Haematoxylin-eosin staining, Siriusred (collagen) staining, immunohistochemistry of CD45-leucocytes, CD3-,CD4-, and CD8-lymfocytes, CD68-macrophages, CD31-capillars, and α-smooth muscle cell-actin coronary arteries. Expression of miR-221 and -222 in the heart will be evaluated with rtPCR and in situ hybridization. 1b. What are the mRNA-targets of miR-221 and -222 in inflammatory cells, fibroblasts and cardiomyocytes? To address which pathways and targets are really functional, and may explain the phenotype observed in in vivo studies, we will combine in vivo and in vitro approaches of pathway analysis and specific target confirmation. We will combine transcriptome, miRNAome and proteome, in order to get gene network analyses and informatics-driven reconstruction of complex interactions. We will perform promoter analysis using Genomatix software (mRNAs and miRs), and we will link mRNA expression to microRNA expression profiles. We intend to investigate whether ERK-1 and/or -2 is a target pathway for miR-221 and -222 in cardiomyocytes versus fibroblasts. We will also investigate and confirm presumed targets by means of TargetScan and MiRanda. Predicted targets for miR-221 and -222 in myocarditis and hypertensive HD could be elements of the cytoskeleton {myosin, actin and sarcoglycan (hypertrophy)}, matrix metalloproteinase-3 (MMP-3)which activates MMP-9 (inflammation and dilatation), smad-2 and -3, involved in transforming growth factor β (fibrosis). These targets will be validated in vitro in miR-221 and -222 (a) overexpressing(by means of lentiviral overexpression), (b) knockdown (using antagomirs), and (c) control cell populations (i.e. monocytes, fibroblasts and cardiomyocytes). Finally, luciferase reporter experiments, wherein 3’-UTR of target-mRNA is ligated to luciferase reporters, will give us theability to confirm these experiments. All necessary logistic and experimental infrastructure is available in the lab. 2. Are miR-221 and -222 useful diagnostic tools and biomarkers for inflammation and for heart failure? Different groups reported that miRNAs are circulating freely in human plasma and serum with marked biostability. Serum profiling performed in routine blood tests opens a window of opportunity for miR biomarker determinations, as RNA detection methods have much higher sensitivity and specificity than currently used protein detection assays (12). We will quantify miR expression in blood and cardiac muscle samples of patients with different kinds of heart failure, compared to a control population. In biopsies, we routinely isolate mRNA (for determination of RNA viruses such as CVB3) in such a way that miRs can also be measured. We will use biopsies of patients with (a) acute ischemia; (b) hypertension; (c) viral myocarditis (in cooperation with prof. dr. A. Frustaci, Rome and prof. dr. H. Schultheiss, Berlin); and (d) control hearts. Already more than 250 blood and cardiac muscle biopsies have been sampled, obtained from patients of the clinicalheart failure unit (UZ Leuven) with ischemic (n=65), hypertensive (n=50) or viral heart disease (n=150). Expected results We expect that our study of miR-221 and -222 in cardiac pathology will lead to a better understanding of their role in inflammatory cardiomyopathies and of viral myocarditis in particular, to a better physiopathological view of hypertrophy and fibrosis in heart failure, to a non-invasive biomarker of heart failure and of viral myocarditis, and eventually toa potential therapeutic target in these settings (13). Embedding of the project Research will be performed in contribution withprof. dr. Peter Carmeliet of the Vesalius Research Center, Flemish Institute for Biotechnology, KULeuven. Bench-to-bedside transformation will be achieved via cooperation with the clinical department of Cardiology UZ Leuven, under guidance of prof. dr. Frans Van de Werf. International collaboration with CARIM (Cardiovascular Research Institute Maastricht) is guaranteed thanks to prof. dr. Stephane Heymans (Maastricht and Leuven), who will help to coordinate this research project. References 1. Schultz JC etal. Diagnosis and treatment of viral myocarditis. Mayo Clin Proc 2009; 84: 1001-9. 2. Dennert R, Crijns HJ and Heymans S. Acute viral myocarditis. Eur Heart J 2008 Jul 9 (epub ahead of print). 3. Heymans S. Inflammation and cardiac remodeling during viral myocarditis. Ernst Schering Res Found Workshop 2006; 55: 197-218. 4. Gilad S et al. Serum microRNAs are promising novel biomarkers. PLoS One 2008: 3; e3148. 5. Grosshans H and Slack FJ. Micro-RNAs: small is plentiful. J Cell Biol 2002; 156: 17-21. 6. Schroen B and Heymans S. MicroRNAs and beyond. The heart reveals its treasures. Hypertension 2009, 54: 1189-94. 7. Latronico MV, Catalucci D, Condorelli G. Emerging role of microRNAs in cardiovascular biology. Circ Res 2007; 101: 1225-36. 8. Worm J et al. Silencing of microRNA-155 in mice during acute inflammatory response leads to derepression of c/ebp Beta and down-regulation of G-CSF. Nucleic Acids Res 2009; 37: 5784-92. 9. Pedersen I, David M. MicroRNAs in theimmune response. Cytokine 2008; 43: 391-94. 10. Krutzfeldt J et al. Silencing of microRNAs in vivo with ‘antagomirs’.Nature 2005; 438: 685-9. 11. Pacak CA et al. Recombinant adeno-associated virus serotype 9 leads to preferential cardiac transduction in vivo. Circ Res 2006; 99: e3-9. 12. Jackson DB. Serum-based microRNAs: are we blinded by potential?Proc Natl Acad Sci 2009; 106: E5. 13. van Rooij E, Marshall WS and Olsen EN. Toward microRNA-based therapeutics for heart disease: the sense in antisense. Circ Res 2008; 103: 919-28.status: publishe

Technology Advances to Improve Response to Cardiac Resynchronization Therapy: What Clinicians Should Know

Cardiac resynchronization therapy (CRT) is a well-established treatment for symptomatic heart failure patients with reduced left ventricular ejection fraction, prolonged QRS duration, and abnormal QRS morphology. The ultimate goals of modern CRT are to improve the proportion of patients responding to CRT and to maximize the response to CRT in patients who do respond. While the rate of CRT nonresponders has moderately but progressively decreased over the last 20 years, mostly in patients with left bundle branch block, in patients without left bundle branch block the response rate is almost unchanged. A number of technological advances have already contributed to achieve some of the objectives of modern CRT. They include novel lead design (the left ventricular quadripolar lead, and multipoint pacing), or the possibility to go beyond conventional delivery of CRT (left ventricular endocardial pacing, His bundle pacing). Furthermore, to improve CRT response, a triad of actions is paramount: reducing the burden of atrial fibrillation, reducing the number of appropriate and inappropriate interventions, and adequately predicting heart failure episodes. As in other fields of cardiology, technology and innovations for CRT delivery have been at the forefront in transforming-improving-patient care; therefore, these innovations are discussed in this review

Diagnosis and immunosuppressive treatment of inflammatory cardiomyopathy : a case report

Objectives: Definite diagnosis of myocarditis requires an endomyocardial biopsy (EMB) showing an inflammatory infiltrate. However, there are important limitations on establishing the diagnosis solely upon histological criteria. The main objective of this case report is to highlight the difficulty of diagnosis, but also to evaluate treatment in virus-negative inflammatory cardiomyopathy. Case report: We present the case of a 53-year-old man with an inflammatory cardiomyopathy based on cardiac magnetic resonance (CMR) findings consistent with extensive myocardial inflammation and a significantly depressed left ventricular ejection fraction (LVEF). Treatment with immunosuppressive therapy resulted in improvement of cardiac function and performance status, while also eliminating the need for ICD implantation. Conclusion: Cardiac magnetic resonance (CMR) has a high diagnostic accuracy and has become the primary diagnostic tool for noninvasive assessment of suspected myocarditis. EMBs should be analyzed using immunohistochemistry and viral polymerase chain reaction to increase the diagnostic sensitivity of histology. Immunosuppressive therapy should be considered in virus-negative inflammatory cardiomyopathy

Anthracycline-Related Heart Failure:Certain Knowledge and Open Questions : Where Do we Stand with Chemotherapyinduced Cardiotoxicity?

In the last decade, cardio-oncology has become a discipline on its own, with tremendous research going on to unravel the mechanisms underpinning different manifestations of cardiotoxicity caused by anticancer drugs. Although this domain is much broader than the effect of chemotherapy alone, a lot of questions about anthracycline-induced cardiotoxicity remain unknown. In this invited review, we provide insights in molecular mechanisms behind anthracycline-induced cardiotoxicity and put it in a clinical framework emphasizing the need for patients to understand, detect, and treat this detrimental condition