Strategy For Treatment Of Heart Failure Research Articles

Empowering Adult Stem Cells for Myocardial Regeneration

Treatment strategies for heart failure remain a high priority for ongoing research due to the profound unmet need in clinical disease coupled with lack of significant translational progress. The underlying issue is the same whether the cause is acute damage, chronic stress from disease, or aging: progressive loss of functional cardiomyocytes and diminished hemodynamic output. To stave off cardiomyocyte losses, a number of strategic approaches have been embraced in recent years involving both molecular and cellular approaches to augment myocardial structure and performance. Resultant excitement surrounding regenerative medicine in the heart has been tempered by realizations that reparative processes in the heart are insufficient to restore damaged myocardium to normal functional capacity and that cellular cardiomyoplasty is hampered by poor survival, proliferation, engraftment, and differentiation of the donated population. To overcome these limitations, a combination of molecular and cellular approaches must be adopted involving use of genetic engineering to enhance resistance to cell death and increase regenerative capacity. This review highlights biological properties of approached to potentiate stem cell-mediated regeneration to promote enhanced myocardial regeneration, persistence of donated cells, and long-lasting tissue repair. Optimizing cell delivery and harnessing the power of survival signaling cascades for ex vivo genetic modification of stem cells before reintroduction into the patient will be critical to enhance the efficacy of cellular cardiomyoplasty. Once this goal is achieved, then cell-based therapy has great promise for treatment of heart failure to combat the loss of cardiac structure and function associated with acute damage, chronic disease, or aging.

New Treatment Strategy for Heart Failure with Preserved Ejection Fraction

New Treatment Strategy for Heart Failure with Preserved Ejection Fraction

CABG and Medical Therapy Perform Equally Well in Patients With Heart Failure

NEW ORLEANS—A trial of 2 treatment strategies for heart failure, one much more expensive and invasive, found that both provide the same degree of protection against death within about 5 years after initiating treatment. Such a finding suggests that cardiologists will opt for the cheaper and less invasive therapy, but that may not be the case. At issue is treatment of patients with coronary artery disease and left ventricular dysfunction. At the American College of Cardiology scientific session here in April, researchers compared the efficacy and safety of coronary artery bypass graft (CABG) surgery plus optimal medical therapy with medical therapy alone. The Surgical Treatment for Ischemic Heart Failure (STICH) trial included 1212 patients with left ventricular ejection fraction of 35% or less and coronary artery disease amenable to CABG, who were randomized to either treatment strategy. After a median follow-up of 56 months, 218 of 610 patients randomized to CABG plus medical therapy died compared with 244 of 602 patients randomized to medical therapy alone; CABG plus medical therapy reduced death rates by 14% compared with medical therapy alone, but the difference did not reach statistical significance (Velazquez EJ et al. N Engl J Med. 2011;364[17]:1607-1616). Those arguing that CABG should remain a viable treatment option for these patients point to secondary analyses showing that those who had the surgery had lower rates of hospitalization for cardiovascular causes or death. Robert O. Bonow, MD, a STICH coinvestigator and a professor of medicine at Northwestern University’s Feinberg School of Medicine in Chicago, pointed out that this is the first prospective randomized study of these types of patients and treatment options and that

Effects of Treatment on Exercise Tolerance, Cardiac Function, and Mortality in Heart Failure With Preserved Ejection Fraction: A Meta-Analysis

We sought to determine whether pharmacologic interventions changed exercise capacity, diastolic function, and mortality in a meta-analysis of trials in heart failure with preserved ejection fraction. Treatment strategies for heart failure with preserved ejection fraction remain unproven despite several large-scale trials. Trials were included in the systematic review where clear comparisons between trial drug and diuretic or placebo were available. Exercise tolerance was assessed by treadmill time, and changes in diastolic function were quantified by transmitral flow (E/A ratio). The primary outcome was all-cause mortality. Weighted mean differences (MDs) and relative risks (RRs), along with their corresponding 95% confidence intervals (CIs), were computed using random-effects models for continuous and dichotomous variables, respectively. The impact of potential covariates was assessed by meta-regression. Data from 53,878 patients enrolled in 30 published reports were collated, including 18 randomized controlled trials (n = 11,253) and 12 observational studies (n = 42,625). In the randomized controlled trials, exercise tolerance was improved by combined therapy (n = 183; weighted MD = 51.5; 95% CI: 27.3 to 75.7; p < 0.001), whereas E/A ratio was not (n = 472; weighted MD = -0.01, 95% CI: -0.02 to 0.02; p = 0.54) even after accounting for baseline E/A (p = 0.87). Over a mean follow-up of 18.6 months, all-cause mortality was not improved by therapy in randomized controlled trials (RR: 0.99, 95% CI: 0.92 to 1.06; p = 0.70), despite accounting for baseline ejection fraction (p = 0.72). In observational reports, there was a reduction in all-cause mortality with therapy in the unadjusted analyses (RR: 0.80, 95% CI: 0.66 to 0.97; p = 0.27), but not after adjustment for clinical and demographic data (RR: 0.93, 95% CI: 0.84 to 1.02; p = 0.10). Pharmacotherapy of heart failure with preserved ejection fraction demonstrates a quantifiable improvement in exercise tolerance but not mortality.

Treatment of Heart Failure with Preserved Ejection Fraction

Heart failure contributes to more than 1 million hospitalizations annually and is one of the most common causes of repeat hospitalizations in the elderly. Previously, it was thought that mortality from heart failure with preserved ejection fraction (PEF) was lower than that from heart failure with reduced ejection fraction (REF), but more recent data infer similar mortality. Although the mortality rate in patients with heart failure with REF is decreasing, the mortality rate in patients with heart failure with PEF remains unchanged--possibly due to the lack of evidence-based treatment regimens or greater recognition of the disease. Without sufficient trials in patients with heart failure with PEF, clinicians are forced to extrapolate treatment from data proven to benefit patients with heart failure with REF. There is no question that clinical trials including only patients with heart failure with PEF are limited. In addition, the definition and clinical diagnosis of this syndrome are not clearly defined, and the guidelines available for treatment lack specificity in recommendations. To describe the current literature for the treatment of heart failure with PEF, we conducted a MEDLINE search of the English-language literature (1950-2009) to identify studies that pertain to the treatment of patients with heart failure with PEF. Ongoing clinical trials continue, but until data become available, clinicians must base their treatment strategies for heart failure with PEF on sparse information.

Pädiatrische Rhythmusstörungen

Diagnosis and therapy of cardiac dysrhythmia has become an important subspecialization in pediatric cardiology. The limited possibilities of antiarrhythmic drug therapy and antibradycardia pacing have been expanded by completely new and fascinating developments over the last 30 years. Curative treatment for the majority of tachyarrhythmias has been achieved by catheter ablation. Secondary as well as primary prevention of sudden arrhythmic death has become possible thanks to implantable defibrillators. Multiple hereditary life-threatening arrhythmia syndromes have been discovered and give a fascinating insight into the molecular genetic background of arrhythmogenesis. Cardiac resynchronization therapy has evolved into one of the few causal treatment strategies for heart failure and points toward intriguing remodeling processes at the cellular level. The following article provides practical as well as background knowledge of some of these developments.

Cardiac Titin

Titin constitutes the third myofilament of cardiac muscle, with a single giant polypeptide spanning from Z-disk to the M-band region of the sarcomere1 (Fig. 1). The ∼1.0 MDa region in the I-band is extensible and consists of tandemly arranged immunoglobulin (Ig)-like domains that make up proximal (near Z-disk) and distal (near A-I junction) segments, interspersed by the PEVK sequence (rich in proline, glutamate, valine, and lysine residues) and the N2B element2. Each functions as a distinct spring element3. The C-terminal ∼2 MDa of titin is located in the A-band and is inextensible. It is composed of regular arrays of Ig and fibronectin type 3 (Fn3) modules forming so-called super-repeats2. A-band titin may function as a molecular ruler, regulating assembly of the thick filament2,4,5. Titin's ∼250-kDa COOH-terminal region is an integral part of the M-band and contains a kinase domain6,7. As in the Z-disk, where titin filaments from opposite sarcomeres overlap, titin filaments from opposite half-sarcomeres overlap within the M-band, where they are interconnected by M-band proteins8. Thus, titin filaments with opposite polarity overlap in both Z-disk and M-band, forming a contiguous filament along the myofibril. In this review, we discuss titin's functions in the heart, with an emphasis on its role in diastolic function and the various mechanisms whereby passive stiffness can be tuned. Due to space constraints, it has not been possible to provide inclusive references to all original articles in the field. Figure 1 Schematic of titin in sarcomere. Differential splicing Titin is encoded by a single gene containing 368 exons. Multiple splice pathways in the I-band encoding region (∼230 exons) give rise to isoforms with different spring composition9. The three cardiac isoform classes are shown in Fig. 1. The relatively small ∼3.0 MDa isoform is known as N2B titin (it contains the N2B element)9. A second class also contains the N2A element, and is termed N2BA titin. N2BA titins have a longer PEVK segment and a variable number of additional Ig domains resulting in a ∼3.3-3.5 MDa size9. The third class includes isoforms that predominate in fetal-neonatal life which contain additional spring elements in both tandem Ig and PEVK regions, resulting in a ∼3.6-3.8 MDa size protein10-12. These isoforms gradually disappear during postnatal development. Regulation of the spring composition of titin in fetal-neonatal myocardium allows adjustment of diastolic filling properties during development.

085 Therapeutic management of heart failure by french outhospital cardiologists is in line with ESH guidelines

HF treatment is often started during hospitalisation. It appeared interesting to describe the evolution of treatment after hospital discharge. To describe changes in HF treatment since hospital discharge after stratification on the time elapsed between discharge and beginning of the survey. Cross sectional observational survey with retrospective collection of data at hospital discharge. Patients must have been diagnosed with HF and have been hospitalised for HF within the previous 18 months. 1452 HF patients met the inclusion criteria and started the survey. 1170 (67% males, age 72±11 years, LVEF 40%±13%) have had at least one visit by the cardiologist between hospital discharge and entry in the survey. Patients were stratified according to the time since hospital discharge (<3 months N=414, 3-6 months N=297, 6-12 months N=296, 12 to 18 months N=163). At hospital discharge, recommended betablocker, ACEI (of which perindopril) or ARB, are prescribed respectively to 826 (70,6%), 807 (69,0%) and 170 (14,5%) patients. Target doses were reached in 87 (10.5%) patients with betablocker, 411 (50.9%) patients with ACEI, 7 (4.1%) patients with ARB and 417 (43.4%) patients with either ACEI or ARB. At start of the survey, target doses were reached in 176 patients (20.4%) treated with betablockers, 470 patients (59.6%) treated with ACEI, 16 patients (7.2%) receiving ARB and 484 patients (49.7%) receiving either ACEI or ARB. Rates of patients reaching the target dose for betablockers increased significantly with time (from 19.5% to 29.8% p=0.01). No significant changes were noticed for ACEI or ARB. Treatment strategies for Heart Failure started at hospital are well followed and amplified by French outhospital cardiologists after hospital discharge.

Mitochondrial oxidative stress and dysfunction in myocardial remodelling

Recent experimental and clinical studies have suggested that oxidative stress is enhanced in myocardial remodelling and failure. The production of oxygen radicals is increased in the failing heart, whereas normal antioxidant enzyme activities are preserved. Mitochondrial electron transport is an enzymatic source of oxygen radical generation and can be a therapeutic target against oxidant-induced damage in the failing myocardium. Chronic increases in oxygen radical production in the mitochondria can lead to a catastrophic cycle of mitochondrial DNA (mtDNA) damage as well as functional decline, further oxygen radical generation, and cellular injury. Reactive oxygen species induce myocyte hypertrophy, apoptosis, and interstitial fibrosis by activating matrix metalloproteinases. These cellular events play an important role in the development and progression of maladaptive myocardial remodelling and failure. Therefore, oxidative stress and mtDNA damage are good therapeutic targets. Overexpression of the genes for peroxiredoxin-3 (Prx-3), a mitochondrial antioxidant, or mitochondrial transcription factor A (TFAM), could ameliorate the decline in mtDNA copy number in failing hearts. Consistent with alterations in mtDNA, the decrease in mitochondrial function was also prevented. Therefore, the activation of Prx-3 or TFAM gene expression could ameliorate the pathophysiological processes seen in mitochondrial dysfunction and myocardial remodelling. Inhibition of oxidative stress and mtDNA damage could be novel and effective treatment strategies for heart failure.

Identification of Cell-Specific Soluble Mediators and Cellular Targets During Cell Therapy for the Treatment of Heart Failure

Cell therapy, the transplantation of progenitor cells into the myocardium, has been proposed as a possible treatment strategy for heart failure. Despite the lack of repopulation of the heart with progenitor cells, cell therapy induces a modest but well-documented functional improvement in patients. It is thought that paracrine mechanisms may account for the observed changes in heart function. However, there is little evidence that directly supports this hypothesis. We discuss the current views in the literature and present some preliminary data proposing that adult progenitor cells influence contractility and Ca2+ handling in neighboring failing cardiomyocytes by soluble mediators. This can be tested using a co-culture system. Our results suggest that soluble mediators from adult progenitor cells can enhance failing cardiomyocyte function, supporting the paracrine hypothesis. This co-culture strategy can be employed to identify cell-specific soluble mediators and their cellular targets during cell therapy for the treatment of heart disease.

Phosphatase inhibitor-1-deficient mice are protected from catecholamine-induced arrhythmias and myocardial hypertrophy

Phosphatase inhibitor-1 (I-1) is a conditional amplifier of beta-adrenergic signalling downstream of protein kinase A by inhibiting type-1 phosphatases only in its PKA-phosphorylated form. I-1 is downregulated in failing hearts and thus contributes to beta-adrenergic desensitization. It is unclear whether this should be viewed as a predominantly adverse or protective response. We generated transgenic mice with cardiac-specific I-1 overexpression (I-1-TG) and evaluated cardiac function and responses to catecholamines in mice with targeted disruption of the I-1 gene (I-1-KO). Both groups were compared with their wild-type (WT) littermates. I-1-TG developed cardiac hypertrophy and mild dysfunction which was accompanied by a substantial compensatory increase in PP1 abundance and activity, confounding cause-effect relationships. I-1-KO had normal heart structure with mildly reduced sensitivity, but unchanged maximal contractile responses to beta-adrenergic stimulation, both in vitro and in vivo. Notably, I-1-KO were partially protected from lethal catecholamine-induced arrhythmias and from hypertrophy and dilation induced by a 7 day infusion with the beta-adrenergic agonist isoprenaline. Moreover, I-1-KO exhibited a partially preserved acute beta-adrenergic response after chronic isoprenaline, which was completely absent in similarly treated WT. At the molecular level, I-1-KO showed lower steady-state phosphorylation of the cardiac ryanodine receptor/Ca(2+) release channel and the sarcoplasmic reticulum (SR) Ca(2+)-ATPase-regulating protein phospholamban. These alterations may lower the propensity for diastolic Ca(2+) release and Ca(2+) uptake and thus stabilize the SR and account for the protection. Taken together, loss of I-1 attenuates detrimental effects of catecholamines on the heart, suggesting I-1 downregulation in heart failure as a beneficial desensitization mechanism and I-1 inhibition as a potential novel strategy for heart failure treatment.

Adriamycin-induced autophagic cardiomyocyte death plays a pathogenic role in a rat model of heart failure

Background The mechanisms underlying heart failure induced by adriamycin are very complicated and still unclear. The aim of this study was to investigate whether autophagy was involved in the progression of heart failure induced by adriamycin, so that we can develop a novel treatment strategy for heart failure. Methods 3-methyladenine (3MA), a specific inhibitor on autophagy was used in a heart failure model of rats induced by adriamycin. Neonatal cardiomyocytes were isolated from Sprague–Dawley rat hearts and randomly divided into controls, an adriamycin-treated group, and a 3MA plus adriamycin-treated group. We then examined the morphology, expression of beclin 1 gene, mitochondrial permeability transition (MPT), and Na +–K + ATPase activity in vivo. We also assessed cell viability, mitochondrial membrane potential changes and counted autophagic vacuoles in cultured cardiomyocytes. In addition, we analyzed the expression of autophagy associated gene, beclin 1 using RT-PCR and Western blotting in an animal model. Results 3MA significantly improved cardiac function and reduced mitochondrial injury. Furthermore, adriamycin induced the formation of autophagic vacuoles, and 3MA strongly downregulated the expression of beclin 1 in adriamycin-induced failing heart and inhibited the formation of autophagic vacuoles. Conclusion Autophagic cardiomyocyte death plays an important role in the pathogenesis of heart failure in rats induced by adriamycin. Mitochondrial injury may be involved in the progression of heart failure caused by adriamycin via the autophagy pathway.

Oxidative Stress and Mitochondrial DNA Damage in Heart Failure

Recent experimental and clinical studies have suggested that oxidative stress is enhanced in heart failure. The production of oxygen radicals is increased in the failing heart while antioxidant enzyme activities are preserved. Mitochondrial electron transport is an enzymatic source of oxygen radical generation and also a target against oxidant-induced damage in the failing myocardium. Chronic increases in oxygen radical production in the mitochondria can lead to a catastrophic cycle of mitochondrial DNA (mtDNA) damage, as well as functional decline, further oxygen radical generation, and cellular injury. Reactive oxygen species induce myocyte hypertrophy, apoptosis, and interstitial fibrosis by activating matrix metalloproteinases. These cellular events play an important role in the development and progression of maladaptive cardiac remodeling and failure. Therefore, oxidative stress and mtDNA damage are good therapeutic targets. Overexpression of peroxiredoxin-3 (Prx-3), mitochondrial antioxidant, or mitochondrial transcription factor A (TFAM) could ameliorate the decline in mtDNA copy number in failing hearts. Consistent with alterations in mtDNA, the decrease in oxidative capacities is also prevented. Therefore, the activation of Prx-3 or TFAM expression could ameliorate the pathophysiological processes seen in myocardial failure. Inhibition of oxidative stress and mtDNA damage could be novel and potentially effective treatment strategies for heart failure.

Human B-type natriuretic peptide – a survey of the patent literature

Background: The human brain natriuretic peptide (hBNP), a cardioprotective hormone released from the heart by cardiomyocytes stretching and neurohormonal activation, emerged as a new biomarker in the diagnosis of congestive heart failure, myocardial ischemia or acute coronary syndrome. BNP in the plasma strikingly increases in left ventricular dysfunction from several causes. Objective: To evaluate hBNP assays in diagnostic, prognostic and guiding treatment strategies in heart failure and other cardiovascular diseases, and to assess the clinical use of recombinant hBNP. Methods: Analysis of hBNP and NT-proBNP as suitable markers for clinical use and application of hBNP in management of acute decompensated heart failure. Results/conclusion: hBNP assays provide useful information for the diagnosis of various heart pathologies, particularly when used with other clinical tests such as echocardiography. They also provide prognostic values for future cardiovascular events. However, use of recombinant BNP for managing acute decompensated heart failure should be limited because it has been associated with both renal dysfunction and increased risk of mortality.

Brain Natriuretic Peptide: Clinical and Research Challenges

Natriuretic peptides, in particular, brain or B-type, are useful for the assessment of patients presenting with dyspnea to the medical office or emergency department. Levels of natriuretic peptides are useful for assessing prognosis of heart failure or coronary syndrome patients. Less is known about serial peptide measurements for guiding treatment strategies in heart failure. The authors review the uses, pitfalls, and practical points for using natriuretic peptides clinically.

Current Guidelines for Treatment of Heart Failure: 2006 Update

Several pivotal clinical trials have generated new knowledge regarding drug therapy for heart failure. Thus, the Heart Failure Society of America (HFSA) and the American College of Cardiology-American Heart Association (ACC-AHA) guidelines were updated in 2006 and 2005, respectively. We review the evidence from these trials and summarize the changes to the HFSA and ACC-AHA guidelines. Based on data from these studies, the new guidelines include broader, stronger recommendations for beta-blocker therapy, and strong recommendations for angiotensin II receptor blockers. The aldosterone antagonists, spironolactone and eplerenone, are also included in the guidelines. Pharmacists should have a basic level of familiarity with the new guidelines on heart failure and the evidence from recent clinical studies. They should be able to relate how this information contributes to the evolving understanding of treatment strategies for heart failure.

Pathophysiology of Volume Overload in Acute Heart Failure Syndromes

The inability to effectively regulate volume status is a major consequence of acute heart failure syndromes (AHFS). A variety of pathophysiologic processes contribute to this impairment, most notably neurohormonal activation of the renin-angiotensin-aldosterone system, arginine vasopressin, and the sympathetic nervous system. As a result, addressing volume overload is one of the most challenging aspects of AHFS management. Neurohormonal activation leads to substantial changes in hemodynamics and myocardial remodeling, which further contribute to the severity of heart failure (HF) disease and thereby cyclically increase the risk of further neurohormonal activation. Pulmonary capillary wedge pressure is a dependable reflection of volume status and has been used as a surrogate marker in recent studies to assess disease progression in response to innovative HF treatment strategies. Future approaches to HF treatment should focus on the more accurate assessment and management of volume status in an effort to improve patient care.

Mitochondrial Oxidative Stress, DNA Damage, and Heart Failure

Recent experimental and clinical studies have suggested that oxidative stress is enhanced in heart failure. The production of oxygen radicals is increased in the failing heart, whereas antioxidant enzyme activities are preserved as normal. Mitochondrial electron transport is an enzymatic source of oxygen radical generation and also a target of oxidant-induced damage. Chronic increases in oxygen radical production in the mitochondria can lead to a catastrophic cycle of mitochondrial DNA (mtDNA) damage as well as functional decline, further oxygen radical generation, and cellular injury. Reactive oxygen species induce myocyte hypertrophy, apoptosis, and interstitial fibrosis by activating matrix metalloproteinases. These cellular events play an important role in the development and progression of maladaptive cardiac remodeling and failure. Therefore, mitochondrial oxidative stress and mtDNA damage are good therapeutic targets. Overexpression of mitochondrial transcription factor A (TFAM) could ameliorate the decline in mtDNA copy number and preserve it at a normal level in failing hearts. Consistent with alterations in mtDNA, the decrease in oxidative capacities was also prevented. Therefore, the activation of TFAM expression could ameliorate the pathophysiologic processes seen in myocardial failure. Inhibition of mitochondrial oxidative stress and mtDNA damage could be novel and potentially very effective treatment strategies for heart failure.

An Introduction to the Collaborative Methodology and Its Potential Use for the Management of Heart Failure

Heart failure (HF) is responsible for significant disease burden in developed countries internationally. Despite significant advances and a strong evidence base in therapies and treatment strategies for HF, access to these therapies continues to remain elusive to a significant proportion of the HF population. The reasons for this are multifactorial and range from the financial cost of treatments to the individual attitudes and beliefs of clinicians. The collaborative methodology, based upon a quality improvement philosophy, has been identified as a potentially useful tool to address this treatment gap. In this manuscript, we review the published literature on the collaborative methodology and assess the evidence for achieving improvement in the management of HF. Searches of electronic databases, the reference lists of published materials, policy documents, and the Internet were conducted using key words including "collaborative methodology," "breakthrough series," "quality improvement," "total quality improvement," and "heart failure." Because of the paucity of high-level evidence, all English-language articles were included in the review. On the basis of the identified search strategy, 43 articles were retrieved. Key themes that emerged from the literature included the following: (1) The collaborative methodology has a significant potential to reduce the treatment gap. (2) Leadership is an important characteristic of the collaborative method. (3) The collaborative methodology facilitates sustainability of the quality improvement process. The collaborative methodology, when implemented and conducted according to key conceptual principles, has significant potential to improve the outcomes of patients, particularly those with HF and chronic cardiovascular disease.

Potential effects of the methods for warming yang and nourishing yin on long-term prognosisof chronic heart failure

Warming yang, which is one of the treatment principles of traditional Chinese Medicine, is very important in treating chronic heart failure, especially late-stage heart failure. It has been proved in many experiments and clinical trials that warming yang can improve the hemodynamic parameters. The treatment strategy for heart failure has changed from short-term correction of hemodynamic parameters to long-term rehabilitation approaches. We discussed the possible negative-effects of warming yang on neuroendocrine responses and myocardial remodeling. The potential beneficial effects of treatment for nourishing yin or nourishing yin combined with warming yang on heart failure were also explored.